Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2
Open accessAbstract
Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
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Written from the paper’s full text.
TL;DR
In high-fat-fed rats with diet-induced hepatic steatosis and insulin resistance, antisense oligonucleotide knockdown of both Acc1 and Acc2 lowered hepatic malonyl-CoA and lipids and improved hepatic insulin sensitivity. The data suggest combined Acc1/Acc2 inhibition may be a therapeutic strategy for NAFLD and hepatic insulin resistance.
Key findings
- Combined Acc1 and -2 ASO reduced hepatic ACC1 and ACC2 mRNA by approximately 80% and total Acc protein by approximately 90%, and lowered malonyl-CoA by 49% (P < 0.05) in refed rat liver; Acc1 or Acc2 ASO alone did not significantly alter malonyl-CoA.
- In high-fat-fed rats, Acc1 and -2 ASO reduced hepatic triglycerides by 45% (P < 0.05), diacylglycerol by 30% (P < 0.05), and long-chain acyl-CoAs by 26% (P = 0.13), and increased fed-state plasma ketones by 83% (P < 0.05) but not fasting ketones.
- Hyperinsulinemic-euglycemic clamps showed Acc1 and -2 ASO increased glucose infusion rates and insulin-mediated suppression of endogenous glucose production, without changing peripheral glucose metabolism; neither Acc1 nor Acc2 ASO alone significantly altered insulin sensitivity, and Acc1 and -2 ASO did not alter insulin sensitivity in chow-fed rats.
- In primary rat hepatocytes, reducing either Acc1 or Acc2 increased fat oxidation, with Acc2 having a greater effect and combined knockdown being synergistic; lipogenesis was inhibited only by Acc1 and combined Acc1 and -2 ASOs, not by Acc2 alone.
Methods
- Male Sprague-Dawley rats were fed chow or a high-fat diet (26% carbohydrate/59% fat/15% protein calories; safflower oil as major constituent); ASO therapy began 3 days after high-fat diet and was given i.p. at 50 mg/kg/wk for 4 weeks.
- Primary rat hepatocytes were transfected with ASO (150 nM) and Lipofectin and assayed for [14C]oleate oxidation and [3H]glycerol incorporation into triglycerides.
- In vivo metabolic assessment used hyperinsulinemic-euglycemic clamps with radioisotope infusions, plus RT-PCR, Western blot, lipid and malonyl-CoA measurements by LC/MS/MS; data analyzed by two-tailed Student’s t tests or 1-way ANOVA with Tukey HSD, significance at P < 0.05.
Limitations
- The paper states that liver-specific Acc reduction did not lower body weight and that longer treatment might be needed for weight reduction; it also notes that ASOs did not alter hypothalamic target expression and no food-intake differences were detected.
- The paper notes prior-model limitations: ACC2-null mice are substantially leaner than wild-type controls, making direct liver effects difficult to discern, and ACC1-null mice are embryonic lethal while ACC1+/- mice appear to have normal hepatocyte Acc1 protein levels.
- Evident from the text: experiments used male Sprague-Dawley rats only, a 4-week high-fat diet model, and small group sizes (often 4–6 rats per group; 6–9 in clamp studies), with no human data.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 31 cited sources checked · 0 supported · 0 flagged
- Findingown data
Acc1 and -2 ASO therapy was associated with increased insulin-stimulated Akt2 activity.
“These changes were associated with increased insulin-stimulated Akt2 activity (Figure 5D)”
Quote in the paperSubstantial claim - Findingown data
In rats with NAFLD, suppression of both enzymes with a single ASO was required to improve hepatic insulin sensitivity.
“In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity.”
Quote in the paperSubstantial claim - Findingown data
Fasting malonyl-CoA levels were similar in all groups.
“Fasting malonyl-CoA levels, which are lower than those in refed rat livers, were similar in all groups (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Suppression of Acc1 inhibited lipogenesis.
“Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis.”
Quote in the paperSubstantial claim - Findingown data
Acc1 and Acc2 ASO treatment reduced ACC1 and ACC2 mRNA levels, respectively, by approximately 80% in the liver compared with ASOctrl.
“In comparison with ASOctrl, Acc1 and Acc2 ASO treatment reduced ACC1 (Figure 1A) and ACC2 mRNA (Figure 1B) levels, respectively, by approximately 80% in the liver.”
Quote in the paperSubstantial claim
- Findingown data
Acc1 and -2 ASO therapy significantly reduced hepatic glucose production (HGP) during the hyperinsulinemic phase of the hyperinsulinemic-euglycemic clamp.
“Acc1 and -2 ASO therapy significantly reduced hepatic glucose production (HGP) during the hyperinsulinemic phase of the hyperinsulinemic-euglycemic clamp (Figure 5, A and B)”
Quote in the paperSubstantial claim - Findingown data
Glucose infusion rates were significantly higher in Acc1 and -2 ASO-treated high-fat-fed rats than in the ASOctrl group.
“Glucose infusion rates were significantly higher in Acc1 and -2 ASO-treated high-fat-fed rats than in the ASOctrl group (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
In vitro fat synthesis was significantly inhibited only by Acc1 ASO and combined Acc1 and -2 ASO.
“In vitro fat synthesis was significantly inhibited only by the Acc1 and Acc1 and -2 ASOs (Figure 2, B and C)”
Quote in the paperSubstantial claim - Findingown data
The ability of insulin to suppress endogenous glucose production was significantly increased by Acc1 and -2 ASO treatment.
“the ability of insulin to suppress endogenous glucose production was significantly increased by Acc1 and -2 ASO treatment (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
Suppression of Acc1 or Acc2 expression with ASOs increased fat oxidation in rat hepatocytes.
“While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation.”
Quote in the paperSubstantial claim - Findingown data
Fasting and refed plasma glucose and fatty acid levels were similar in both groups.
“Fasting and refed plasma glucose and fatty acid levels were similar in both groups (Table 1)”
Quote in the paperNot a substantial claim - Findingown data
Acc1 and -2 ASO therapy was associated with increased FoxO1 phosphorylation.
“and forkhead transcription factor FoxO1 (Foxo1) phosphorylation (Figure 5E).”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO substantially lowered malonyl-CoA levels in the liver of refed rats (49% reduction, P < 0.05).
“the Acc1 and -2 ASO substantially lowered (49%, P < 0.05) malonyl-CoA levels in the liver of refed rats (Figure 1F).”
Quote in the paperSubstantial claim - Findingown data
No significant reductions in Acc expression were found with any ASO-treated groups in muscle.
“In contrast to the liver, no significant reductions were found with any of the ASO-treated groups in muscle, consistent with previous findings (Figure 1, C and D) (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15]
Not checked in the free run.
- Findingown data
Both Acc1 and Acc2 are involved in regulating fat oxidation in the liver.
“The results suggest that both Acc1 and Acc2 are involved in regulating fat oxidation in the liver, whereas only Acc1 synthe-sizes malonyl-CoA for fat synthesis, and that reducing both Acc1 and Acc2 expression with a single Acc ASO (Acc1 and -2) reverses hepatic steatosis and hepatic insulin resistance in high-fat-fed rats, providing a novel therapeutic option for the treatment of NAFLD.”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO substantially lowered (49%, P < 0.05) malonyl-CoA levels in the liver of refed rats.
“Malonyl-CoA levels were not significantly altered by Acc1 or Acc2 ASO therapy, whereas the Acc1 and -2 ASO substantially lowered (49%, P < 0.05) malonyl-CoA levels in the liver of refed rats”
Quote in the paperSubstantial claim - Findingown data
Acc2 reduction had no effect on lipogenesis.
“Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis.”
Quote in the paperSubstantial claim - Findingown data
The increase in fat oxidation was significantly greater with Acc2 ASO than with Acc1 ASO in primary rat hepatocytes.
“although the effect was significantly greater with the Acc2 ASO”
Quote in the paperNot a substantial claim- Rests on an assumption: Acc2 regulates malonyl-CoA levels in the immediate proximity of CPT1.
- Findingown data
Acc1 is the dominant isoform, at least in terms of protein expression, in rat liver.
“Western blotting also suggested that Acc1 is the dominant isoform, at least in terms of protein expression, in rat liver.”
Quote in the paperNot a substantial claim - Findingown data
Acc1 and -2 ASO therapy significantly reduced PKCε membrane translocation.
“and significantly reduced PKCε membrane translocation (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
Only Acc1 synthesizes malonyl-CoA for fat synthesis.
“The results suggest that both Acc1 and Acc2 are involved in regulating fat oxidation in the liver, whereas only Acc1 synthe-sizes malonyl-CoA for fat synthesis, and that reducing both Acc1 and Acc2 expression with a single Acc ASO (Acc1 and -2) reverses hepatic steatosis and hepatic insulin resistance in high-fat-fed rats, providing a novel therapeutic option for the treatment of NAFLD.”
Quote in the paperSubstantial claim - Findingown data
Reduction of either Acc1 or Acc2 significantly increased fat oxidation in primary rat hepatocytes.
“Reduction of either Acc1 or Acc2 significantly increased fat oxidation, although the effect was significantly greater with the Acc2 ASO”
Quote in the paperSubstantial claim - Findingown data
Reducing both Acc1 and Acc2 expression with a single Acc ASO reverses hepatic steatosis and hepatic insulin resistance in high-fat-fed rats.
“The results suggest that both Acc1 and Acc2 are involved in regulating fat oxidation in the liver, whereas only Acc1 synthe-sizes malonyl-CoA for fat synthesis, and that reducing both Acc1 and Acc2 expression with a single Acc ASO (Acc1 and -2) reverses hepatic steatosis and hepatic insulin resistance in high-fat-fed rats, providing a novel therapeutic option for the treatment of NAFLD.”
Quote in the paperSubstantial claim - Findingown data
Hepatic TGs were significantly lower in Acc1 and -2-treated animals than in controls (45% reduction, P < 0.05).
“Hepatic TGs were significantly lower in Acc1 and -2-treated animals than in controls (45% reduction; P < 0.05) (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
DAG levels were significantly reduced in Acc1 and -2 ASO-treated animals (30% reduction, P < 0.05).
“diacylglycerol (DAG) levels were significantly (30% reduction; P < 0.05) reduced in Acc1 and -2 ASOtreated animals (Figure 3, B and C).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of both Acc1 and Acc2 isoforms synergistically increased fat oxidation.
“knockdown of both isoforms synergistically increased fat oxidation (Figure 2A)”
Quote in the paperSubstantial claim - Findingown data
In rats with NAFLD, suppression of both enzymes with a single ASO was required to lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides).
“In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity.”
Quote in the paperSubstantial claim - Findingown data
Insulin-stimulated peripheral glucose metabolism was similar in both groups.
“insulin-stimulated peripheral glucose metabolism was similar in both groups (Figure 4B)”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 therapy did not alter peripheral or hepatic insulin sensitivity in chow-fed (control diet) rats.
“Acc1 and -2 therapy did not alter peripheral or hepatic insulin sensitivity in chow-fed (control diet) rats (Figure 4, A-C).”
Quote in the paperSubstantial claim - Findingown data
Suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation than suppression of either alone.
“While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation.”
Quote in the paperSubstantial claim - Findingown data
LCCoA tended to be lower in Acc1 and -2 ASO-treated animals (26% reduction, P = 0.13).
“LCCoA also tended to be lower (26% reduction; P = 0.13)”
Quote in the paperNot a substantial claim - Findingown data
Insulin-mediated suppression of PEPCK and G6P mRNA expression was significantly increased in Acc1 and -2 ASO-treated rats.
“insulin-mediated suppression of their expression was significantly increased in Acc1 and -2 ASO-treated rats (Figure 5, F and G)”
Quote in the paperSubstantial claim - Findingown data
Plasma ALT levels in Acc1 and -2 ASO-treated rats were within the range seen in healthy chow-fed rats.
“Plasma alanine aminotransferase (ALT) levels were within the range seen in healthy chow-fed rats (Table 1)”
Quote in the paperSubstantial claim - Findingown data
Refed plasma insulin and leptin levels were significantly reduced in Acc1 and -2 ASO-treated rats.
“refed plasma insulin and leptin levels were significantly reduced in Acc1 and -2 ASO-treated rats.”
Quote in the paperSubstantial claim - Findingown data
Treatment with Acc1 and -2 ASO reduced both ACC1 and ACC2 mRNA by approximately 80% in the liver.
“Whereas Acc1 and Acc2 ASOs reduced target expression in an Acc isoform-specific manner, treatment with the Acc1 and -2 ASO reduced both ACC1 and ACC2 mRNA by approximately 80% (Figure 1, A and B).”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO treatment does not alter basal HGP in high-fat-fed rats.
“Acc1 and -2 ASO treatment does not alter basal HGP (A)”
Quote in the paperNot a substantial claim - Findingown data
Target reduction in the liver with the lead ASO revealed approximately 80% reduction of both ACC1 and ACC2 mRNA.
“Target reduction in the liver revealed approximately 80% reduction of both ACC1 and ACC2 mRNA with the lead ASO.”
Quote in the paperSubstantial claim - Findingreasoning
Reduction of Acc2 in addition to Acc1 has no further inhibitory effect on lipogenesis.
“Reduction of Acc2 in addition to Acc1 has no further inhibitory effect on lipogenesis.”
Quote in the paperSubstantial claim - Findingreasoning
Acc1 and -2 ASO therapy increased Foxo1 phosphorylation.
“this increased Foxo1 phosphorylation”
Quote in the paperSubstantial claim - Findingown data
Plasma ketones (β-OHB) are significantly increased in Acc1 and -2 ASO-treated rats in the fed state.
“but are significantly increased in Acc1 and -2-treated rats in the fed state (E)”
Quote in the paperNot a substantial claim - Findingreasoning
Acc1 and -2 ASO therapy improved insulin-stimulated suppression of gluconeogenic gene expression.
“improved insulin-stimulated suppression of gluconeogenic gene expression”
Quote in the paperSubstantial claim - Findingnone given
Acc1 is the dominant isoform in rat liver.
“In summary, the current study suggests that both Acc1 and Acc2 are involved in regulating fat oxidation in hepatocytes while Acc1, the dominant isoform in rat liver, is the sole regulator of fatty acid synthesis.”
Quote in the paperSubstantial claim - Findingown data
Reduction of Acc1 alone significantly increased fat oxidation.
“Reduction of Acc1 alone also significantly increased fat oxidation”
Quote in the paperSubstantial claim - Findingown data
Acc1 and Acc2 ASOs selectively reduced ACC1 or ACC2 mRNA and protein expression in hepatocytes.
“The results show that Acc1 and Acc2 ASOs selectively reduced ACC1 or ACC2 mRNA and protein expression in hepatocytes.”
Quote in the paperSubstantial claim - Findingown data
No differences in food intake were detected.
“we did not detect any differences in food intake”
Quote in the paperSubstantial claim - Findingreasoning
Plasma ketones increased in this model.
“the increase in plasma ketones”
Quote in the paperSubstantial claim - Findingown data
Reduction of Acc1 alone inhibited fat synthesis.
“inhibited fat synthesis”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO therapy decreased LCCoA accumulation.
“Acc1 and -2 ASO therapy decreased TG, LCCoA, and DAG accumulation”
Quote in the paperSubstantial claim - Findingreasoning
Acc1 and -2 ASO therapy reduced PKCε membrane translocation.
“reduced PKCε membrane translocation”
Quote in the paperSubstantial claim - Findingown data
Acc ASOs lower malonyl-CoA levels in rat liver.
“Acc ASOs decrease ACC expression and lower malonyl-CoA levels in rat liver.”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO therapy decreased DAG accumulation.
“Acc1 and -2 ASO therapy decreased TG, LCCoA, and DAG accumulation”
Quote in the paperSubstantial claim - Findingreasoning
Acc1 and -2 ASO therapy improved insulin-stimulated Akt2 activity.
“improved insulin-stimulated Akt2 activity”
Quote in the paperSubstantial claim - Findingown data
Acc ASOs decrease ACC expression in rat liver.
“Acc ASOs decrease ACC expression and lower malonyl-CoA levels in rat liver.”
Quote in the paperSubstantial claim - Findingreasoning
Acc inhibition in the liver in rats does not lower body weight.
“Acc inhibition in the liver in rats does not lower body weight”
Quote in the paperNot a substantial claim - Findingown data
Acc1 and -2 ASO treatment enhances insulin-mediated suppression of HGP in high-fat-fed rats.
“but enhances insulin-mediated suppression of HGP in high-fat-fed rats (B)”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO treatment is associated with increased Foxo1 phosphorylation.
“and increased Foxo1 phosphorylation”
Quote in the paperSubstantial claim - Findingown data
Reduction of Acc1 alone did not detectably alter hepatic malonyl-CoA levels.
“without detectably altering hepatic malonyl-CoA levels”
Quote in the paperSubstantial claim - Findingcitation
Intraperitoneally administered ASOs used in this study do not alter target gene expression in the hypothalamus.
“the intraperitoneally administered ASOs used in this study do not alter target gene expression in the hypothalamus”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15]
Not checked in the free run.
- Findingreasoning
Simultaneously knocking down both Acc isoforms has a synergistic effect on fatty acid oxidation.
“synergistic effect on fatty acid oxidation of simultaneously knocking down both Acc isoforms”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO treatment suppresses hepatic PEPCK mRNA expression during hyperinsulinemic-euglycemic clamps.
“(F) Suppression of hepatic PEPCK mRNA and (G) G6P mRNA expression during hyperinsulinemic-euglycemic clamps.”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO therapy lowers hepatic lipid levels in rats.
“Acc1 and -2 ASO therapy lowers hepatic lipid levels in rats.”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO treatment suppresses hepatic G6P mRNA expression during hyperinsulinemic-euglycemic clamps.
“(F) Suppression of hepatic PEPCK mRNA and (G) G6P mRNA expression during hyperinsulinemic-euglycemic clamps.”
Quote in the paperSubstantial claim - Findingown data
Acc1 and -2 ASO treatment is associated with increased Akt2 activity.
“This change is associated with increased Akt2 activity (D)”
Quote in the paperSubstantial claim - Findingreasoning
Reduction of Acc1 and Acc2 expression had no further effect on fasting ketone levels.
“reduction of Acc1 and Acc2 expression had no further effect on fasting ketone levels”
Quote in the paperNot a substantial claim - Findingreasoning
The rise in plasma ketones was only detectable in the fed state.
“the rise in plasma ketones was only detectable in the fed state”
Quote in the paperNot a substantial claim - Findingown data
Plasma ketones (β-OHB) are similar in control and Acc1 and -2 ASO-treated rats in the fasting state.
“Plasma ketones (β-hydroxybutyrate [β-OHB]) are similar in control and Acc1 and -2 ASO-treated rats in the fasting state (D)”
Quote in the paperNot a substantial claim - Findingown data
Acc1 and -2 ASO therapy does not significantly lower hepatic LCCoA levels (P = 0.13).
“LCCoAs (P = 0.13)”
Quote in the paperNot a substantial claim - Findingown data
Acc1 and -2 ASO therapy decreased TG accumulation.
“Acc1 and -2 ASO therapy decreased TG, LCCoA, and DAG accumulation”
Quote in the paperSubstantial claim - Interpretationreasoning
Lipid accumulation in the liver is directly responsible for the subsequent development of hepatic insulin resistance and increased endogenous glucose production.
“Together, these data strongly suggest that lipid accumulation in the liver is directly responsible for the subsequent development of hepatic insulin resistance and increased endogenous glucose production, key elements in the pathogenesis of type 2 diabetes.”
Quote in the paperSubstantial claim - Premisecitation
Malonyl-CoA is a key physiological regulator of both fatty acid synthesis and oxidation.
“Malonyl-CoA is therefore a key physiological regulator of both fatty acid synthesis (10) and oxidation (11).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10]
Not checked in the free run.
- cites [11]
Not checked in the free run.
- Interpretationown data
At the doses used, inhibition of Acc does not cause hepatic toxicity.
“suggesting that at the doses used, inhibition of Acc does not cause hepatic toxicity.”
Quote in the paperSubstantial claim - Interpretationown data
Pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
“These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.”
- Also stated in: § Introduction · plain
“providing a novel therapeutic option for the treatment of NAFLD.”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Premisecitation
Activation of PKCε may be causally related to the development of hepatic insulin resistance.
“an event which we believe may be causally related to the development of hepatic insulin resistance (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6]
Not checked in the free run.
- Premisecitation
Foxo1 phosphorylation prevents Foxo1 from entering the nucleus and binding to promoters of target genes, such as PEPCK and G6P.
“Foxo1 phosphorylation prevents Foxo1 from entering the nucleus and binding to promoters of target genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6 phosphatase (G6P) (17,18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [17]
Not checked in the free run.
- cites [18]
Not checked in the free run.
- Premisecitation
NAFLD is associated with activation of PKCε, as reflected by an increase in the plasma membrane/cytosol ratio of PKCε.
“We have previously shown that NAFLD is associated with activation of PKCε as reflected by an increase in the plasma membrane/cytosol ratio of PKCε”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6]
Not checked in the free run.
- Interpretationreasoning
Malonyl-CoA generated in the cytosol via Acc1 contributes to CPT1 regulation.
“This observation suggests that malonyl-CoA generated in the cytosol (via Acc1) also contributes to CPT1 regulation”
Quote in the paperSubstantial claim - Interpretationown data
Lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state.
“Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state.”
Quote in the paperSubstantial claim - Interpretationown data
Acc2 may regulate malonyl-CoA levels in a localized pool in the proximity of CPT1.
“Acc2 may regulate malonyl-CoA levels in a localized pool in the proximity of CPT1”
Quote in the paperSubstantial claim - Interpretationown data
Acc1 and -2 ASO therapy improves hepatic insulin signaling.
“Acc1 and -2 ASO therapy improves hepatic insulin signaling.”
Quote in the paperSubstantial claim - Premisecitation
In high-fat-fed rats, hepatic lipid accumulation is primarily a consequence of fatty acid re-esterification rather than de novo lipogenesis.
“this is primarily a consequence of fatty acid re-esterification rather than de novo lipogenesis”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6]
Not checked in the free run.
- Interpretationown data
Acc1 and -2 ASO treatment significantly improved hepatic insulin sensitivity in high-fat-fed rats.
“Acc1 and -2 ASO treatment significantly improved hepatic insulin sensitivity in high-fat-fed rats.”
Quote in the paperSubstantial claim - Interpretationreasoning
Acc1 has a dominant role in regulating de novo lipogenesis.
“The dominant role of Acc1 in regulating de novo lipogenesis”
Quote in the paperSubstantial claim - Interpretationown data
Acc1 and -2 ASO treatment improves hepatic insulin sensitivity.
“Acc1 and -2 ASO treatment improves hepatic insulin sensitivity.”
Quote in the paperSubstantial claim - Interpretationown data
Both Acc1 and Acc2 are involved in regulating fat oxidation in hepatocytes.
“In summary, the current study suggests that both Acc1 and Acc2 are involved in regulating fat oxidation in hepatocytes while Acc1, the dominant isoform in rat liver, is the sole regulator of fatty acid synthesis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Hepatic Acc1 and -2 inhibitors may be useful in the treatment of NAFLD and hepatic insulin resistance.
“Thus, hepatic Acc1 and -2 inhibitors may be useful in the treatment of NAFLD and hepatic insulin resistance.”
Quote in the paperSubstantial claim- Rests on an assumption: The rat high-fat diet model of hepatic steatosis and insulin resistance is predictive of human NAFLD and hepatic insulin resistance.
- Premisecitation
The 2′-MOE chimeric ASO design results in an attractive in vivo pharmacological and toxicological profile.
“These benefits result in an attractive in vivo pharmacological and toxicological profile for 2′-MOE chimeric ASOs.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35]
Not checked in the free run.
- Interpretationreasoning
The increased insulin-mediated suppression of PEPCK and G6P mRNA expression explains, at least in part, the reduction in HGP during the hyperinsulinemic phase of the clamp.
“explaining, at least in part, the reduction in HGP during the hyperinsulinemic phase of the clamp.”
Quote in the paperSubstantial claim- Rests on an assumption: PEPCK and G6P are key regulators of hepatic glucose production.
- Rests on an assumption: Insulin suppresses endogenous glucose production, at least in part, by lowering mRNA levels of PEPCK and G6P.
- Interpretationown data
In this model, combined reduction of both Acc1 and Acc2 is required to increase fat oxidation in the fed state.
“Furthermore, in this model, combined reduction of both isoforms is required to significantly lower hepatic malonyl-CoA levels, increase fat oxidation in the fed state, reduce lipid accumulation, and improve insulin action in vivo.”
Quote in the paperSubstantial claim - Interpretationreasoning
The in vivo effects of the Acc1 and -2 ASO are predominantly a result of increased fat oxidation rather than a tendency to inhibit fat synthesis in this model.
“the in vivo effects of the Acc1 and -2 ASO are predominantly a result of increased fat oxidation rather than a tendency to inhibit fat synthesis in this model”
Quote in the paperSubstantial claim - Interpretationown data
In this model, combined reduction of both Acc1 and Acc2 is required to improve insulin action in vivo.
“Furthermore, in this model, combined reduction of both isoforms is required to significantly lower hepatic malonyl-CoA levels, increase fat oxidation in the fed state, reduce lipid accumulation, and improve insulin action in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
After 4 weeks of high-fat feeding in rats, re-esterification remains the dominant factor in the development of steatosis.
“re-esterification remains the dominant factor in the development of steatosis in high-fat-fed rats”
Quote in the paperSubstantial claim - Interpretationreasoning
This study directly assessed the biological roles of each Acc isoform in the liver for the first time.
“enabling us to directly assess the biological roles of each isoform in the liver for what we believe is the first time.”
Quote in the paperSubstantial claim - Interpretationown data
In this model, combined reduction of both Acc1 and Acc2 is required to reduce lipid accumulation.
“Furthermore, in this model, combined reduction of both isoforms is required to significantly lower hepatic malonyl-CoA levels, increase fat oxidation in the fed state, reduce lipid accumulation, and improve insulin action in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
In this model, combined reduction of both Acc1 and Acc2 is required to significantly lower hepatic malonyl-CoA levels.
“Furthermore, in this model, combined reduction of both isoforms is required to significantly lower hepatic malonyl-CoA levels, increase fat oxidation in the fed state, reduce lipid accumulation, and improve insulin action in vivo.”
Quote in the paperSubstantial claim - Interpretationnone given
Acc1 is the sole regulator of fatty acid synthesis.
“In summary, the current study suggests that both Acc1 and Acc2 are involved in regulating fat oxidation in hepatocytes while Acc1, the dominant isoform in rat liver, is the sole regulator of fatty acid synthesis.”
Quote in the paperNot a substantial claim - Interpretationown data
Acc1 and -2 ASO reduces hepatic steatosis.
“Acc1 and -2 ASO reduces hepatic steatosis.”
Quote in the paperSubstantial claim
- May combine two claims. 22
- Classified as probably not a substantial claim. 17
May combine two claims.
Findingown dataNeither the Acc1 nor the Acc2 ASO significantly altered insulin sensitivity.
“Neither the Acc1 nor the Acc2 ASO significantly altered insulin sensitivity (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI27300DS1).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningPlasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state.
“Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingown dataMalonyl-CoA levels were not significantly altered by Acc1 or Acc2 ASO therapy in the liver of refed rats.
“Malonyl-CoA levels were not significantly altered by Acc1 or Acc2 ASO therapy, whereas the Acc1 and -2 ASO substantially lowered (49%, P < 0.05) malonyl-CoA levels in the liver of refed rats”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataWestern blot analysis confirmed isoform-selective knockdown of Acc protein expression and approximately 90% knockdown of total Acc protein with the Acc1 and -2 ASO.
“Western blot analysis of liver protein extracts from rats injected with the Acc1, Acc2, and combined Acc1 and -2 ASOs confirmed isoform-selective knockdown of Acc protein expression and approximately 90% knockdown of total Acc protein with the Acc1 and -2 ASO (Figure 1E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataASO-induced inhibition of Acc2 in rat hepatocytes significantly increased fat oxidation without altering malonyl-CoA levels in tissue extracts.
“ASO-induced inhibition of Acc2 in rat hepatocytes significantly increased fat oxidation without altering malonyl-CoA levels in tissue extracts”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe effects of Acc ASOs were isoform specific and tissue selective, with no apparent compensatory increase in the nontargeted isoform.
“The effects were both isoform specific and tissue selective, and there was no apparent compensatory increase in the nontargeted isoform”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAcc ASOs also reduced ACC expression in adipose tissue (~80%) but not in muscle.
“Acc ASOs also reduced ACC expression in adipose tissue (∼80%, data not shown) but not in muscle.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLowering Acc expression in adipose tissue did not alter epididymal fat-pad weight, body weight, plasma-free fatty acids, or 2-deoxyglucose uptake in adipose tissue.
“lowering Acc expression in adipose tissue did not alter epididymal fat-pad weight, body weight, plasma-free fatty acids, or 2-deoxyglucose uptake in adipose tissue (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOverexpressing lipoprotein lipase (LPL) in the liver in mice results in fatty liver and liver-specific insulin resistance.
“Overexpressing lipoprotein lipase (LPL) in the liver in mice results in fatty liver and liver-specific insulin resistance (5).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5]
Not checked in the free run.
May combine two claims.
PremisecitationModerate weight loss in humans with type 2 diabetes lowers liver TGs and specifically improves hepatic insulin sensitivity.
“We have also shown that moderate weight loss in humans with type 2 diabetes lowers liver TGs and specifically improves hepatic insulin sensitivity (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe most common disorder associated with NAFLD is insulin resistance, an association that holds true in both lean and obese subjects.
“The most common disorder associated with NAFLD is insulin resistance, an association which holds true in both lean and obese subjects (3,4).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3]
Not checked in the free run.
- cites [4]
Not checked in the free run.
May combine two claims.
PremisecitationShort-term high-fat feeding in rats leads to hepatic steatosis, impaired insulin signaling, and hepatic insulin resistance.
“Short-term high-fat feeding in rats leads to hepatic steatosis, impaired insulin signaling, and hepatic insulin resistance, and reducing lipid accumulation with a mitochondrial uncoupling agent (2,4-dinitrophenol) improves hepatic insulin sensitivity (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationAcetyl-CoA carboxylase (Acc) catalyzes the synthesis of malonyl-CoA.
“Acetyl-CoA carboxylase (Acc) catalyzes the synthesis of malonyl-CoA, which is both an intermediate in fatty acid synthesis and an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1) (8,9).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8]
Not checked in the free run.
- cites [9]
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningReducing liver lipid accumulation may be an attractive therapeutic strategy for NAFLD and type 2 diabetes.
“They also suggest that reducing liver lipid accumulation may be an attractive therapeutic strategy for NAFLD and type 2 diabetes.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationMalonyl-CoA is both an intermediate in fatty acid synthesis and an allosteric inhibitor of CPT1.
“Acetyl-CoA carboxylase (Acc) catalyzes the synthesis of malonyl-CoA, which is both an intermediate in fatty acid synthesis and an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1) (8,9).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8]
Not checked in the free run.
- cites [9]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReducing lipid accumulation with a mitochondrial uncoupling agent (2,4-dinitrophenol) improves hepatic insulin sensitivity in rats.
“Short-term high-fat feeding in rats leads to hepatic steatosis, impaired insulin signaling, and hepatic insulin resistance, and reducing lipid accumulation with a mitochondrial uncoupling agent (2,4-dinitrophenol) improves hepatic insulin sensitivity (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6]
Not checked in the free run.
May combine two claims.
Study design and conductown dataCaloric intake and weight gain were similar in all treated groups and did not differ from those of high-fat-fed rats injected with saline.
“Caloric intake and weight gain were similar in all treated groups and did not differ from those of high-fat-fed rats injected with saline.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThe reduction in leptin levels during the fed state probably reflects the lower insulin levels.
“The reduction in leptin levels during the fed state probably reflects the lower insulin levels (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationACC2-null mice are leaner than wild-type controls due to increased fat oxidation in heart and skeletal muscle.
“ACC2-null mice (ACC2 -/-) are leaner than wild-type controls due to increased fat oxidation in heart and skeletal muscle (12).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHepatic fat oxidation was increased and hepatic steatosis decreased in ACC2 -/- mice despite normal malonyl-CoA levels.
“Interestingly, hepatic fat oxidation was also increased and hepatic steatosis decreased in ACC2 -/-mice despite normal malonyl-CoA levels; the authors postulated that this might have been a consequence of localized lowering of malonyl-CoA”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationACC1-null mice are embryonic lethal.
“ACC1-null mice are embryonic lethal (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe primary structural difference between ACC1 and ACC2 is an extra N terminal hydrophobic domain in Acc2 that appears to facilitate Acc2 localization to the mitochondrial membrane.
“The primary structural difference between the 2 is an extra N terminal hydrophobic domain in Acc2 that appears to facilitate Acc2 localization to the mitochondrial membrane (13), where it is believed to regulate local malonyl-CoA levels, CPT1 activity, and fat oxidation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13]
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThere are 2 isoforms of Acc in rodents and humans; Acc1 is highly expressed in liver and adipose tissue whereas Acc2 is predominantly expressed in heart and skeletal muscle and, to a lesser extent, in the liver.
“There are 2 isoforms of Acc in rodents and humans; Acc1 is highly expressed in liver and adipose tissue whereas Acc2 is predominantly expressed in heart and skeletal muscle and, to a lesser extent, in the liver (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationAcc2 localization to the mitochondrial membrane is believed to regulate local malonyl-CoA levels, CPT1 activity, and fat oxidation.
“The primary structural difference between the 2 is an extra N terminal hydrophobic domain in Acc2 that appears to facilitate Acc2 localization to the mitochondrial membrane (13), where it is believed to regulate local malonyl-CoA levels, CPT1 activity, and fat oxidation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13]
Not checked in the free run.
May combine two claims.
Interpretationown dataAcc2 is solely involved in regulating fat oxidation, whereas Acc1 contributes to regulation of both fat synthesis and fat oxidation in hepatocytes.
“suggesting that Acc2 is solely involved in regulating fat oxidation whereas Acc1 contributes to the regulation of both fat synthesis and fat oxidation in hepatocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: Acc2 regulates malonyl-CoA levels in the immediate proximity of CPT1.
May combine two claims.
Study design and conductown dataCaloric intake, total weight gain, and epididymal fat pad weight were similar in all treated groups and did not differ from high-fat-fed rats injected with saline.
“Caloric intake, total weight gain, and epididymal fat pad weight were similar in all treated groups (Table 1) and did not differ from those of high-fat-fed rats injected with saline (data not shown).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMalonyl-CoA produced by Acc1 appears to regulate both fatty acid synthesis and fatty acid oxidation, whereas Acc2 is solely involved in regulating mitochondrial fat oxidation.
“malonyl-CoA produced by Acc1 appears to regulate both fatty acid synthesis and fatty acid oxidation, whereas Acc2 is solely involved in regulating mitochondrial fat oxidation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe adiponectin kit showed significant cross-reactivity with rat adiponectin.
“The adiponectin kit was primarily designed to measure mouse adiponectin, but showed significant cross-reactivity with rat adiponectin.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe high-fat diet used in this study produces hepatic steatosis and hepatic insulin resistance within 3 days in rats.
“We have previously shown that this diet produces hepatic steatosis and hepatic insulin resistance within 3 days (6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6]
Not checked in the free run.
May combine two claims.
InterpretationreasoningWith time, a relatively modest increase in fat oxidation in the fed state results in lower liver lipid levels and improved hepatic insulin sensitivity.
“with time a relatively modest increase in fat oxidation in the fed state results in lower liver lipid levels and improved hepatic insulin sensitivity”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe control ASO ISIS-141923 does not have perfect complementarity to any known gene in public databases.
“It does not have perfect complementarity to any known gene in public databases.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe Yale Animal Care and Use Committee approved all protocols.
“The Yale Animal Care and Use Committee approved all protocols.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe 2′-MOE chimeric ASO design provides increased nuclease resistance and mRNA affinity while maintaining the RNase H terminating mechanism.
“This chimeric design has been shown to provide both increased nuclease resistance and mRNA affinity while maintaining the robust RNase H terminating mechanism utilized by these types of ASOs (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35]
Not checked in the free run.
May combine two claims.
PremisecitationHepatic lipid accumulation causes hepatic insulin resistance and contributes to the pathogenesis of type 2 diabetes.
“It is becoming increasingly clear that hepatic lipid accumulation causes hepatic insulin resistance and contributes to the pathogenesis of type 2 diabetes (2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll rats were maintained in accordance with the institutional Animal Use and Care Committees of Yale University School of Medicine.
“All rats were maintained in accordance with the institutional Animal Use and Care Committees of Yale University School of Medicine.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIncreased Foxo1 phosphorylation promotes nuclear exclusion of Foxo1, thereby lowering its transcriptional activity on the promoters of gluconeogenic genes such as PEPCK and G6P.
“which promotes nuclear exclusion of Foxo1, thereby lowering its transcriptional activity on the promoters of gluconeogenic genes, such as PEPCK and G6P.”
Quote in the paperSubstantial claim
The paper relies on this without support.
ACC1 and ACC2 exhibit considerable sequence identity (~85% excluding the N terminal extension of ACC2) and have the same domain structure responsible for enzyme activity.
“Despite being encoded by separate genes, ACC1 and ACC2 exhibit considerable sequence identity (∼85% excluding the N terminal extension of ACC2) and have the same domain structure responsible for enzyme activity.”
The paper relies on this without support.
Acc1 is localized in the cytosol, where it regulates lipogenesis in the liver and adipose tissue.
“Acc1 is localized in the cytosol, where it is thought to regulate lipogenesis in the liver and adipose tissue.”
The paper relies on this without support.
CPT1 regulates the transfer of long-chain acyl-CoAs from the cytosol into the mitochondria, where they are oxidized.
“CPT1 regulates the transfer of long-chain acyl-CoAs (LCCoAs) from the cytosol into the mitochondria, where they are oxidized.”
The paper relies on this without support.
Insulin resistance is a key element in the pathogenesis of type 2 diabetes and the metabolic syndrome.
“Insulin resistance is in turn a key element in the pathogenesis of type 2 diabetes and the metabolic syndrome.”
The paper relies on this without support.
Acc2 regulates malonyl-CoA levels in the immediate proximity of CPT1.
“which is believed to regulate malonyl-CoA levels in the immediate proximity of CPT1.”
The paper relies on this without support.
PEPCK and G6P are key regulators of hepatic glucose production.
“PEPCK and G6P are key regulators of HGP”
The paper relies on this without support.
Insulin suppresses endogenous glucose production, at least in part, by lowering mRNA levels of PEPCK and G6P.
“insulin suppresses endogenous glucose production, at least in part, by lowering mRNA levels of PEPCK and G6P.”
The paper relies on this without support.
Acc catalyzes a key rate-controlling step in both de novo lipogenesis and fatty acid oxidation.
“Acc catalyzes a key rate-controlling step in both de novo lipogenesis and fatty acid oxidation.”
The paper relies on this without support.
Plasma ketones are synthesized in the liver from acetyl-CoA derived from fatty acid oxidation and can be used as an indirect marker of hepatic fatty acid oxidation.
“Plasma ketones are synthesized in the liver from acetyl-CoA derived from fatty acid oxidation and can, therefore, be used as an indirect marker of hepatic fatty acid oxidation.”
The paper relies on this without support.
The hypothesis that cytosolic Acc1 regulates malonyl-CoA synthesis for incorporation into fatty acids, whereas Acc2 regulates mitochondrial fatty acid oxidation, has never been directly tested.
“this hypothesis has never been directly tested”
The paper relies on this without support.
The rat high-fat diet model of hepatic steatosis and insulin resistance is predictive of human NAFLD and hepatic insulin resistance.
“Thus, hepatic Acc1 and -2 inhibitors may be useful in the treatment of NAFLD and hepatic insulin resistance.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM.
“recent studies have demonstrated that NAFLD-induced hepatic insulin resistance is a major factor responsible for the transition from normoglycemia to fasting hyperglycemia and T2DM (18–23).”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [23]
NAFLD is strongly linked to hepatic insulin resistance.
“NAFLD is strongly linked to hepatic insulin resistance”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [23]
Nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.
“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [26]
Increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of protein kinase C epsilon, resulting in reduced insulin signaling and hepatic insulin resistance.
“Recent studies have shown that increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of the protein kinase C epsilon isoform, resulting in reduced insulin signaling and hepatic insulin resistance.23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [26]
In this setting, PKCε, but not other isoforms of PKC, is activated.
“In this setting, PKCε, but not other isoforms of PKC, is activated.”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [12]
Preventing fat accumulation by inhibiting lipid synthesis via disruption of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase or promoting fat oxidation using either mitochondrial uncoupler 2,4-dinitrophenol or inhibition of acetyl-CoA carboxylase-1 and -2 prevents PKCε activation and hepatic insulin resistance.
“Preventing fat accumulation by inhibiting lipid synthesis via disruption of the mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase (7) or promoting fat oxidation using either the mitochondrial uncoupler 2,4-dinitrophenol (10) or inhibition of acetyl-CoA carboxylase-1 and -2 (12) prevents PKCε activation and hepatic insulin resistance.”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [12]
Preventing fat accumulation in rodents preserves hepatic insulin action.
“Preventing fat accumulation in rodents preserves hepatic insulin action (7,10,12).”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [12]
DAG concentrations have closely paralleled insulin resistance in other models.
“This is important since DAG is a known activator of classic and novel isoforms of PKC and DAG concentrations have closely paralleled insulin resistance in other models (7,12).”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [12]
DAG is a known activator of classic and novel isoforms of PKC.
“This is important since DAG is a known activator of classic and novel isoforms of PKC and DAG concentrations have closely paralleled insulin resistance in other models (7,12).”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [12]
There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance in rodent models and in patients with nonalcoholic fatty liver disease.
“There is increasing evidence for a causal relationship between hepatic steatosis and hepatic insulin resistance both in rodent models with hepatic steatosis and in patients with nonalcoholic fatty liver disease (4, 18-25).”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [25]
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751 · see citing works
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/y59-099 · Cited by 23,189 · see citing works
Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery
Sjöström, L., Lindroos, A.-K., Peltonen, M., Torgerson, J., Bouchard, C., Carlsson, B., Dahlgren, S., Larsson, B., Narbro, K., Sjöström, C. D., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa035622 · Cited by 4,457 · see citing works
Prevalence of Hepatic Steatosis in An Urban Population in the United States: Impact of Ethnicity
Browning, J. D., Szczepaniak, L. S., Dobbins, R., Nuremberg, P., Horton, J. D., Cohen, J. C., Grundy, S. M., & Hobbs, H. H. (2004) · Hepatology · doi:10.1002/hep.20466 · Cited by 3,664 · see citing works
Mechanism of activation of protein kinase B by insulin and IGF‐1.
Alessi, D. R., Andjelković, M., Caudwell, B., Cron, P. D., MORRICE, N. A., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,007 · see citing works
Cellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714 · see citing works
Molecular mediators of hepatic steatosis and liver injury
Browning, J. D., & Horton, J. D. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422422 · Cited by 1,772 · see citing works
The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis
McGarry, J. D., & Brown, N. F. (1997) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1997.00001.x · Cited by 1,616 · see citing works
Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561 · see citing works
(2004) · doi:10.1016/s0092-8674(04)00452-0 · Cited by 1,356 · see citing works
Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322 · see citing works
Leptin-Replacement Therapy for Lipodystrophy
Oral, E. A., Simha, V., Ruiz, E., Andewelt, A., Premkumar, A., Snell, P., Wagner, A. J., DePaoli, A. M., Reitman, M. L., Taylor, S. I., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa012437 · Cited by 1,247 · see citing works
Transient increase in obese gene expression after food intake or insulin administration
Saladin, R., Vos, P. D., Guerre-Millo, M., Leturque, A., Girard, J. R., Staels, B., & Auwerx, J. H. (1995) · Nature · doi:10.1038/377527a0 · Cited by 1,093 · see citing works
Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy
Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S., & Goldstein, J. L. (1999) · Nature · doi:10.1038/43448 · Cited by 1,038 · see citing works
FATTY ACID SYNTHESIS AND ITS REGULATION
Wakil, S. J., Stoops, J. K., & Joshi, V. C. (1983) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.52.070183.002541 · Cited by 1,029 · see citing works
Petersen, K. F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005) · Diabetes · doi:10.2337/diabetes.54.3.603 · Cited by 911 · see citing works
Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2
Abu-Elheiga, L., Matzuk, M. M., Abo-Hashema, K. A. H., & Wakil, S. J. (2001) · Science · doi:10.1126/science.1056843 · Cited by 903 · see citing works
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121164498 · Cited by 753 · see citing works
Savage, D. B., Sewter, C. P., Klenk, E. S., Segal, D. G., Vidal‐Puig, A., Considine, R. V., & O’Rahilly, S. (2001) · Diabetes · doi:10.2337/diabetes.50.10.2199 · Cited by 748 · see citing works
Self-citationLeptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy
Petersen (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215001 · Cited by 622 · see citing works
Frescas, D., Valenti, L. N., & Accili, D. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412357200 · Cited by 554 · see citing works
The subcellular localization of acetyl-CoA carboxylase 2
Abu-Elheiga, L. A., Brinkley, W. R., Zhong, L., Chirala, S. S., Woldegiorgis, G., & Wakil, S. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1444 · Cited by 450 · see citing works
An, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., & Newgard, C. B. (2004) · Nature Medicine · doi:10.1038/nm995 · Cited by 450 · see citing works
Metabolic Significance of Nonalcoholic Fatty Liver Disease in Nonobese, Nondiabetic Adults
Kim, H. J., Kim, H. J., Lee, K. E., Kim, D. J., Kim, S. K., Ahn, C. W., Lim, S., Kim, K. R., Lee, H. C., Huh, K. B., et al. (2004) · Archives of Internal Medicine · doi:10.1001/archinte.164.19.2169 · Cited by 434 · see citing works
Yu, X. X., Murray, S. F., Pandey, S., Booten, S. L., Bao, D., Song, X., Kelly, S., Chen, S., McKay, R. A., Monia, B. P., et al. (2005) · Hepatology · doi:10.1002/hep.20783 · Cited by 303 · see citing works
Regulation of mammalian acetyl-CoA carboxylase
Munday, M. R. (2002) · Biochemical Society Transactions · doi:10.1042/bst0301059 · Cited by 301 · see citing works
Mechanisms of Insulin Resistance in Humans and Possible Links With Inflammation
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2005) · Hypertension · doi:10.1161/01.hyp.0000163475.04421.e4 · Cited by 284 · see citing works
Self-citationHypothalamic malonyl-CoA as a mediator of feeding behavior
Hu, Z., Cha, S. H., Chohnan, S., & Lane, M. D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834402100 · Cited by 272 · see citing works
Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal
Abu-Elheiga, L. A., Matzuk, M. M., Kordari, P., Oh, W. K., Shaiken, T. E., Gu, Z., & Wakil, S. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505714102 · Cited by 263 · see citing works
Neschen, S., Morino, K., Hammond, L. E., Zhang, D., Liu, Z.-X., Romanelli, A. J., Cline, G. W., Pongratz, R. L., Zhang, X.-M., Choi, C. S., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.006 · Cited by 261 · see citing works
Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years After Bariatric Surgery
McGoldrick, K. E. (2005) · Survey of Anesthesiology · doi:10.1097/01.sa.0000165261.51330.8f · Cited by 241 · see citing works
McKay, R. A., Miraglia, L. J., Cummins, L. L., Owens, S. R., Sasmor, H. M., & Dean, N. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.3.1715 · Cited by 220 · see citing works
Seppala-Lindroos, A. (2002) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.7.3023 · Cited by 168 · see citing works
Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content
Neschen, S., Moore, I. K., Regittnig, W., Yu, C. L., Wang, Y., Pypaert, M., Petersen, K. F., & Shulman, G. I. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00414.2001 · Cited by 155 · see citing works
Considine, R. V., Nyce, M. R., Allen, L. E., Morales, L. M., Triester, S., Serrano, J., Colberg, J., Lanza-Jacoby, S., & Caro, J. F. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118001 · Cited by 141 · see citing works
Watts, L. M., Manchem, V. P., Leedom, T. A., Rivard, A. L., McKay, R. A., Bao, D., Neroladakis, T., Monia, B. P., Bodenmiller, D. M., Cao, J. X. C., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1846 · Cited by 136 · see citing works
Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition
Harwood, H. J., Jr. (2005) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.9.2.267 · Cited by 127 · see citing works
Friedman, J. M. (2002) · Nature · doi:10.1038/415268a · Cited by 126 · see citing works
Qu, X.-Q., Seale, J., & Donnelly, R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1620207 · Cited by 123 · see citing works
The regulation of Acetyl-CoA carboxylase—a potential target for the action of hypolipidemic agents
Munday, M. R., & Hemingway, C. J. (1999) · Advances in Enzyme Regulation · doi:10.1016/s0065-2571(98)00016-8 · Cited by 99 · see citing works
Ishigaki, Y., Katagiri, H., Yamada, T., Ogihara, T., Imai, J., Uno, K., Hasegawa, Y., Gao, J., Ishihara, H., Shimosegawa, T., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.2.322 · Cited by 70 · see citing works
Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice
Buettner, C., Patel, R. D., Muse, E. D., Bhanot, S., Monia, B. P., McKay, R., Obici, S., & Rossetti, L. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23109 · Cited by 68 · see citing works
Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance?
Shmueli, E., Alberti, K. G. M. M., & Record, C. O. (1993) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.1993.tb00761.x · Cited by 61 · see citing works
Leptin-Replacement Therapy in Lipodystrophy
Wolfsdorf, J. I., Sadeghi‐Nejad, A., & Senior, B. (2002) · New England Journal of Medicine · doi:10.1056/nejm200206203462515 · Cited by 61 · see citing works
Regulation of mammalian acetyl-CoA carboxylase
Munday, M. R. (2002) · Biochemical Society Transactions · doi:10.1042/bst030a101c · Cited by 18 · see citing works
Mechanisms of Insulin Resistance
Salans, L. B., Wardzala, L. J., Simpson, I. A., Karnieli, E., Hissin, P. J., & Cushman, S. W. (2015) · Frontiers in diabetes · doi:10.1159/000408866 · Cited by 1 · see citing works
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Energy Metabolism in the Liver
Rui, L. (2014) · Comprehensive physiology · doi:10.1002/cphy.c130024 · Cited by 2,258 · see citing works
Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications
Fabbrini, E., Sullivan, S., & Klein, S. (2010) · Hepatology · doi:10.1002/hep.23280 · Cited by 2,100 · see citing works
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990 · see citing works
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,633 · see citing works
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484 · see citing works
Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease
Ipsen, D. H., Lykkesfeldt, J., & Tveden-Nyborg, P. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2860-6 · Cited by 1,471 · see citing works
Obesity-associated improvements in metabolic profile through expansion of adipose tissue
Kim, J.-Y., van de Wall, E., Laplante, M., Azzara, A., Trujillo, M. E., Hofmann, S. M., Schraw, T., Durand, J. L., Li, H., Li, G., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31021 · Cited by 1,310 · see citing works
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J., et al. (2014) · Nature · doi:10.1038/nature13270 · Cited by 1,284 · see citing works
Triglyceride Metabolism in the Liver
Alves‐Bezerra, M., & Cohen, D. E. (2017) · Comprehensive physiology · doi:10.1002/cphy.c170012 · Cited by 1,229 · see citing works
Postic, C., & Girard, J. R. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34275 · Cited by 1,200 · see citing works
Lipid-induced insulin resistance: unravelling the mechanism
Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60408-4 · Cited by 1,189 · see citing works
Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes
Muoio, D. M., & Newgard, C. B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2327 · Cited by 1,177 · see citing works
Insulin Resistance: From Mechanisms to Therapeutic Strategies
Lee, S.-H., Park, S., & Choi, C. S. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0280 · Cited by 1,179 · see citing works
The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry, R. J., Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2014) · Nature · doi:10.1038/nature13478 · Cited by 1,136 · see citing works
Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease
Shulman, G. I. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1011035 · Cited by 1,126 · see citing works
Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease
Kawano, Y., & Cohen, D. E. (2013) · Journal of Gastroenterology · doi:10.1007/s00535-013-0758-5 · Cited by 968 · see citing works
Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z.-P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3372 · Cited by 893 · see citing works
Morino, K., Petersen, K. F., & Shulman, G. I. (2006) · Diabetes · doi:10.2337/db06-s002 · Cited by 853 · see citing works
Cellular and Molecular Mechanisms of Metformin Action
LaMoia, T. E., & Shulman, G. I. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa023 · Cited by 791 · see citing works
Kim, K. H., Jeong, Y. T., Oh, H., Kim, S. H., Cho, J. M., Kim, Y.-N., Kim, S. S., Kim, D. H., Hur, K. Y., Kim, H. K., et al. (2013) · Nature Medicine · doi:10.1038/nm.3014 · Cited by 774 · see citing works
The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome
Lim, J. S., Mietus-Snyder, M., Valente, A., Schwarz, J.-M., & Lustig, R. H. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.41 · Cited by 771 · see citing works
The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome
Petersen, K. F., Dufour, S., Savage, D. B., Bilz, S., Solomon, G., Yonemitsu, S., Cline, G. W., Befroy, D., Zemany, L., Kahn, B. B., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705408104 · Cited by 759 · see citing works
Self-citationNonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745 · see citing works
“Fructose is metabolized almost exclusively by the liver, and therefore ingested fructose is funneled into the liver and mostly metabolized to triglycerides by DNL (Herman and Samuel, 2016).”
InfluentialFatty acid metabolism: Target for metabolic syndrome
Wakil, S. J., & Abu-Elheiga, L. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800079-jlr200 · Cited by 731 · see citing works
Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease
Softic, S., Cohen, D. E., & Kahn, C. R. (2016) · Digestive Diseases and Sciences · doi:10.1007/s10620-016-4054-0 · Cited by 709 · see citing works
Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)
Musso, G., Gambino, R. J., & Cassader, M. (2008) · Progress in Lipid Research · doi:10.1016/j.plipres.2008.08.001 · Cited by 678 · see citing works
Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance
Meex, R. C. R., & Watt, M. J. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.56 · Cited by 631 · see citing works
De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose
Sanders, F., & Griffin, J. L. (2015) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12178 · Cited by 543 · see citing works
Svensson, R. U., Parker, S. J., Eichner, L. J., Kolar, M. J., Wallace, M., Brun, S. N., Lombardo, P. S., Van Nostrand, J. L., Hutchins, A., Vera, L., et al. (2016) · Nature Medicine · doi:10.1038/nm.4181 · Cited by 536 · see citing works
Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association
Bays, H. E., Toth, P. P., Kris-Etherton, P. M., Abate, N., Aronne, L. J., Brown, W. V., Gonzalez-Campoy, J. M., Jones, S. R., Kumar, R., La Forge, R., et al. (2013) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2013.04.001 · Cited by 521 · see citing works
Treatment of nonalcoholic fatty liver disease: role of AMPK
Smith, B. K., Marcinko, K., Desjardins, E. M., Lally, J., Ford, R. J., & Steinberg, G. R. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00225.2016 · Cited by 502 · see citing works
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497 · see citing works
Diacylglycerol-mediated insulin resistance
Erion, D. M., & Shulman, G. I. (2010) · Nature Medicine · doi:10.1038/nm0410-400 · Cited by 493 · see citing works
Taylor, R. (2013) · Diabetes Care · doi:10.2337/dc12-1805 · Cited by 485 · see citing works
Structure and function of biotin-dependent carboxylases
Tong, L. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1096-0 · Cited by 473 · see citing works
Wilson, C. G., Tran, J. L., Erion, D. M., Vera, N. B., Febbraio, M., & Weiss, E. J. (2015) · Endocrinology · doi:10.1210/en.2015-1866 · Cited by 461 · see citing works
Loss of Metabolic Flexibility in the Failing Heart
Karwi, Q. G., Uddin, G. M., Ho, K. L., & Lopaschuk, G. D. (2018) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2018.00068 · Cited by 441 · see citing works
Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease
Petersen, K. F., Dufour, S., Hariri, A., Nelson-Williams, C., Foo, J. N., Zhang, X.-M., Dziura, J., Lifton, R. P., & Shulman, G. I. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907295 · Cited by 428 · see citing works
Genetic control of de novo lipogenesis: role in diet-induced obesity
Strable, M. S., & Ntambi, J. M. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409231003667500 · Cited by 415 · see citing works
Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men
Petersen, K. F., Dufour, S., Feng, J., Befroy, D., Dziura, J., Man, C. D., Cobelli, C., & Shulman, G. I. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608537103 · Cited by 403 · see citing works
Lipogenesis inhibitors: therapeutic opportunities and challenges
Batchuluun, B., Pinkosky, S. L., & Steinberg, G. R. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00367-2 · Cited by 401 · see citing works
Kars, M., Yang, L., Gregor, M. F., Mohammed, B. S., Pietka, T., Finck, B. N., Patterson, B. W., Horton, J. D., Mittendorfer, B., Hotamışlıgil, G. S., et al. (2010) · Diabetes · doi:10.2337/db10-0308 · Cited by 400 · see citing works
Choi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704213200 · Cited by 383 · see citing works
Self-citationAMPK inhibition in health and disease
Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M., Giri, S., & Andreelli, F. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2010.488215 · Cited by 383 · see citing works
Roles of diacylglycerols and ceramides in hepatic insulin resistance
Petersen, M. C., & Shulman, G. I. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.04.004 · Cited by 373 · see citing works
Dai, J., Liang, K., Zhao, S., Jia, W., Liu, Y., Wu, H., Lv, J., Cao, C., Chen, T., Zhuang, S., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801745115 · Cited by 339 · see citing works
STAT3 inhibition of gluconeogenesis is downregulated by SirT1
Nie, Y., Erion, D. M., Yuan, Z., Dietrich, M. O., Shulman, G. I., Horváth, T. L., & Gao, Q. (2009) · Nature Cell Biology · doi:10.1038/ncb1857 · Cited by 331 · see citing works
Choi, C. S., Savage, D. B., Abu-Elheiga, L., Liu, Z.-X., Kim, S., Kulkarni, A., Distefano, A., Hwang, Y.-J., Reznick, R. M., Codella, R., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706794104 · Cited by 325 · see citing works
Self-citationDiacylglycerol Activation of Protein Kinase Cε and Hepatic Insulin Resistance
Jornayvaz, F. R., & Shulman, G. I. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.005 · Cited by 315 · see citing works
Jeong, W., Osei‐Hyiaman, D., Park, O., Liu, J., Bátkai, S., Mukhopadhyay, P., Horiguchi, N., Harvey-White, J. D., Marsicano, G., Lutz, B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.12.007 · Cited by 311 · see citing works
Acetyl-CoA metabolism in cancer
Guertin, D. A., & Wellen, K. E. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00543-5 · Cited by 303 · see citing works
Regulatory enzymes of mitochondrial β‐oxidation as targets for treatment of the metabolic syndrome
Schreurs, M., Kuipers, F., & van der Leij, F. R. (2009) · Obesity Reviews · doi:10.1111/j.1467-789x.2009.00642.x · Cited by 295 · see citing works
Mao, J., DeMayo, F. J., Huiguang, L., Abu-Elheiga, L. A., Gu, Z., Shaiken, T. E., Kordari, P., Chirala, S. S., Heird, W. C., & Wakil, S. J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603115103 · Cited by 292 · see citing works
The ins and outs of endoplasmic reticulum‐controlled lipid biosynthesis
Jacquemyn, J., Cascalho, A. C. C., & Goodchild, R. E. (2017) · EMBO Reports · doi:10.15252/embr.201643426 · Cited by 289 · see citing works
The role of the lipogenic pathway in the development of hepatic steatosis
Postic, C., & Girard, J. R. (2008) · Diabetes & Metabolism · doi:10.1016/s1262-3636(08)74599-3 · Cited by 287 · see citing works
Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance
Asrih, M., & Jornayvaz, F. R. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0201 · Cited by 284 · see citing works
Hepatic triacylglycerol accumulation and insulin resistance
Nagle, C. A., Klett, E. L., & Coleman, R. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800053-jlr200 · Cited by 272 · see citing works
Schwarz, J., Noworolski, S. M., Erkin‐Cakmak, A., Korn, N. J., Wen, M., Tai, V., Jones, G. M., Palii, S. P., Velasco-Alin, M., Pan, K. D. H., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.05.043 · Cited by 272 · see citing works
Free radical biology for medicine: learning from nonalcoholic fatty liver disease
Serviddio, G., Bellanti, F., & Vendemiale, G. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.08.174 · Cited by 269 · see citing works
Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R., Paul, D., Tong, L., Saha, A. K., Westlin, W. F., Kapeller, R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520686113 · Cited by 287 · see citing works
Role of Insulin Resistance and Lipotoxicity in Non-Alcoholic Steatohepatitis
Cusi, K. J. (2009) · Clinics in Liver Disease · doi:10.1016/j.cld.2009.07.009 · Cited by 263 · see citing works
Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease
Dong, B., Saha, P., Huang, W., Chen, W., Abu-Elheiga, L. A., Wakil, S. J., Stevens, R. D., Ilkayeva, O., Newgard, C. B., Chan, L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909731106 · Cited by 262 · see citing works
Fructose induced lipogenesis: from sugar to fat to insulin resistance
Samuel, V. T. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.10.003 · Cited by 261 · see citing works
Goedeke, L., Bates, J. G., Vatner, D. F., Perry, R. J., Wang, T., Ramírez, R., Li, L., Ellis, M. W., Zhang, D., Wong, K. E., et al. (2018) · Hepatology · doi:10.1002/hep.30097 · Cited by 257 · see citing works
Metabolic disturbances in non-alcoholic fatty liver disease
Byrne, C. D., Olufadi, R., Bruce, K. D., Cagampang, F. R. A., & Ahmed, M. H. (2009) · Clinical Science · doi:10.1042/cs20080253 · Cited by 255 · see citing works
Hepatic triglyceride synthesis and nonalcoholic fatty liver disease
Choi, S. S., & Diehl, A. M. (2008) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3282ff5e55 · Cited by 254 · see citing works
The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis
Herman, M. A., & Samuel, V. T. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.06.005 · Cited by 249 · see citing works
Non-Alcoholic Fatty Liver Disease
Engin, A. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_19 · Cited by 247 · see citing works
Mitochondrial fatty acid oxidation in obesity
Serra, D., Mera, P., Malandrino, M. I., Mir, J. F., & Herrero, L. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4875 · Cited by 246 · see citing works
A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects
Lee, J. M., Lee, Y., Mamrosh, J. L., Busby, S. A., Griffin, P. R., Pathak, M. C., Ortlund, E. A., & Moore, D. D. (2011) · Nature · doi:10.1038/nature10111 · Cited by 241 · see citing works
Nonalcoholic Fatty Liver Disease: Focus on Lipoprotein and Lipid Deregulation
Tacer, K. F., & Rozman, D. (2011) · Journal of Lipids · doi:10.1155/2011/783976 · Cited by 232 · see citing works
Bates, J., Vijayakumar, A., Ghoshal, S., Marchand, B., Yi, S., Kornyeyev, D., Zagorska, A., Hollenback, D., Walker, K., Liu, K., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.04.037 · Cited by 230 · see citing works
Komiya, C., Tsuchiya, K., Shiba, K., Miyachi, Y., Furuke, S., Shimazu, N., Yamaguchi, S., Kanno, K., & Ogawa, Y. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151511 · Cited by 230 · see citing works
Murase, T., Misawa, K., Minegishi, Y., Aoki, M., Ominami, H., Suzuki, Y., Shibuya, Y., & Hase, T. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00441.2010 · Cited by 228 · see citing works
High Sugar-Induced Insulin Resistance in Drosophila Relies on the Lipocalin Neural Lazarillo
Pasco, M. Y., & Léopold, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036583 · Cited by 225 · see citing works
Acetyl-CoA Carboxylases and Diseases
Wang, Y., Yu, W., Li, S., Guo, D., He, J., & Wang, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.836058 · Cited by 225 · see citing works
Metabolic drivers of non-alcoholic fatty liver disease
Bence, K. K., & Birnbaum, M. J. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101143 · Cited by 223 · see citing works
Calle, R. A., Amin, N. B., Carvajal-Gonzalez, S., Ross, T. T., Bergman, A., Aggarwal, S., Crowley, C., Rinaldi, A., Mancuso, J., Aggarwal, N., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01489-1 · Cited by 219 · see citing works
Lawitz, E. J., Coste, A., Poordad, F., Alkhouri, N., Loo, N., McColgan, B. J., Tarrant, J. M., Nguyen, T., Han, L., Chung, C., et al. (2018) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.04.042 · Cited by 217 · see citing works
Santoro, N., Kursawe, R., D’Adamo, E., Dykas, D. J., Zhang, C. K., Bale, A. E., Cali, A. M. G., Narayan, D., Shaw, M. M., Pierpont, B. M., et al. (2010) · Hepatology · doi:10.1002/hep.23832 · Cited by 214 · see citing works
Wang, Q. A., Jiang, L., Wang, J., Li, S., Yu, Y., You, J., Zeng, R., Gao, X., Rui, L., Li, W., et al. (2008) · Hepatology · doi:10.1002/hep.22774 · Cited by 212 · see citing works
Jornayvaz, F. R., Jurczak, M. J., Lee, H., Birkenfeld, A. L., Frederick, D. W., Zhang, D., Zhang, X., Samuel, V. T., & Shulman, G. I. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00361.2010 · Cited by 212 · see citing works
Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor
Lin, H., Yu, I.-C. I., Wang, R.-S., Chen, Y., Liu, N.-C., Altuwaijri, S., Hsu, C., Ma, W., Jokinen, J. D., Sparks, J. D., et al. (2008) · Hepatology · doi:10.1002/hep.22252 · Cited by 210 · see citing works
Romeo, S., Sentinelli, F., Dash, S., Yeo, G. S. H., Savage, D. B., Leonetti, F., Capoccia, D., Incani, M., Maglio, C., Iacovino, M., et al. (2009) · International Journal of Obesity · doi:10.1038/ijo.2009.216 · Cited by 209 · see citing works
Self-citationAcetyl-coenzyme A carboxylases: versatile targets for drug discovery
Tong, L., & Harwood, H. J. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21077 · Cited by 207 · see citing works
Nagai, Y., Yonemitsu, S., Erion, D. M., Iwasaki, T., Stark, R., Weismann, D., Dong, J., Zhang, D., Jurczak, M. J., Löffler, M. G., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.01.011 · Cited by 203 · see citing works
Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia
Morrow, M. R., Batchuluun, B., Wu, J., Ahmadi, E., Leroux, J. M., Mohammadi-Shemirani, P., Desjardins, E. M., Wang, Z., Tsakiridis, E. E., Lavoie, D. C. T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.05.004 · Cited by 199 · see citing works
De novo lipogenesis in metabolic homeostasis: More friend than foe?
Solinas, G., Borén, J., & Dulloo, A. G. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.03.004 · Cited by 197 · see citing works
Adiels, M., Westerbacka, J., Soro‐Paavonen, A., Häkkinen, A. ‐., Vehkavaara, S., CASLAKE, M. J., Packard, C. J., Olofsson, S.-O., Yki‐Järvinen, H., Taskinen, M., et al. (2007) · Diabetologia · doi:10.1007/s00125-007-0790-1 · Cited by 197 · see citing works
Hepatic Steatosis as a Marker of Metabolic Dysfunction
Fabbrini, E., & Magkos, F. (2015) · Nutrients · doi:10.3390/nu7064995 · Cited by 191 · see citing works
Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury
Ussher, J. R., Wang, W., Gandhi, M., Keung, W., Samokhvalov, V., Oka, T., Wagg, C. S., Jaswal, J. S., Harris, R. A., Clanachan, A. S., et al. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs129 · Cited by 184 · see citing works
Choi, C. S., Fillmore, J. J., Kim, J. K., Liu, Z., Kim, S., Collier, E. F., Kulkarni, A. S., Distefano, A. G., Hwang, Y.-J., Kahn, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci13579 · Cited by 182 · see citing works
Heat-stress abatement during the dry period: Does cooling improve transition into lactation?
do Amaral, B. C., Connor, E. E., Tao, S., Hayen, J., Bubolz, J. W., & Dahl, G. E. (2009) · Journal of Dairy Science · doi:10.3168/jds.2009-2343 · Cited by 179 · see citing works
Gusdon, A. M., Song, K., & Qu, S. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/637027 · Cited by 171 · see citing works
Lipid oversupply, selective insulin resistance, and lipotoxicity: Molecular mechanisms
Chavez, J. A., & Summers, S. A. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.09.015 · Cited by 167 · see citing works
IL-1 Signaling in Obesity-Induced Hepatic Lipogenesis and Steatosis
Negrin, K. A., Flach, R. J. R., DiStefano, M. T., Matevossian, A., Friedline, R. H., Jung, D., Kim, J. K., & Czech, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107265 · Cited by 166 · see citing works
Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship
Karkucińska‐Więckowska, A., Simões, I. C. M., Kalinowski, P., Lebiedzińska, M., Zieniewicz, K., Milkiewicz, P., Górska‐Ponikowska, M., Pinton, P., Malik, A. N., Krawczyk, M. J., et al. (2021) · European Journal of Clinical Investigation · doi:10.1111/eci.13622 · Cited by 165 · see citing works
Alkhouri, N., Lawitz, E., Noureddin, M., DeFronzo, R., & Shulman, G. I. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1668374 · Cited by 162 · see citing works
Insulin signaling to hepatic lipid metabolism in health and disease
Leavens, K. F., & Birnbaum, M. J. (2011) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2011.562481 · Cited by 162 · see citing works
Physiological functions of peroxisome proliferator-activated receptor β
Neels, J. G., & Grimaldi, P. A. (2014) · Physiological Reviews · doi:10.1152/physrev.00027.2013 · Cited by 161 · see citing works
- Authors
- Savage, D. B.
- Affiliations
- Yale University (US)
- Corresponding author
- Savage, D. B.
- ORCID
- Savage, D. B.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-03-01
- Volume
- 116
- Issue
- 3
- Pages
- 817-824
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1366503
- OpenAlex
- W2168436114
- Semantic Scholar
- b60a71456837361b15d6f178e59b8779765b0f90
- Cited by
- 447
- References
- 48
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 21 · 2021: 17 · 2020: 25 · 2019: 14 · 2018: 27 · 2017: 17 · 2016: 27 · 2015: 20 · 2014: 27 · 2013: 21 · 2012: 28
- FWCI
- 23.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- Wellcome Trust
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, P30DK045735)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- acetyl-CoA carboxylase 1, acetyl-CoA carboxylase 2, antisense oligonucleotides, hepatic steatosis, non-alcoholic fatty liver disease, hepatic insulin resistance, malonyl-CoA, fatty acid oxidation, lipogenesis, metabolic syndrome, type 2 diabetes, plasma ketones, hepatocytes
- MeSH terms
- Acetyl-CoA Carboxylase, Animals, Diet, Enzyme Inhibitors, Fatty Acids, Fatty Liver, Insulin Resistance, Triglycerides, Signal Transduction, Oligonucleotides, Antisense, Hepatocytes, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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