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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.
Overview
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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.
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Claims the paper makes
62 Own result · 26 Not checked yet · 26 Own interpretation · 12 No basis given · 6 Own method
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In the paper
“These changes were associated with increased insulin-stimulated Akt2 activity (Figure 5D)”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Effect of Acc1 and -2 ASO treatment on hepatic insulin signaling.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Abstract
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In the paper
“Fasting malonyl-CoA levels, which are lower than those in refed rat livers, were similar in all groups (data not shown).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Effect of Acc1 and -2 ASO treatment on hepatic insulin signaling.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Glucose infusion rates were significantly higher in Acc1 and -2 ASO-treated high-fat-fed rats than in the ASOctrl group (Figure 4A).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc1 and -2 ASO reduces hepatic steatosis.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In vitro fat synthesis was significantly inhibited only by the Acc1 and Acc1 and -2 ASOs (Figure 2, B and C)”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the ability of insulin to suppress endogenous glucose production was significantly increased by Acc1 and -2 ASO treatment (Figure 4C).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc1 and -2 ASO reduces hepatic steatosis.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 22
- Probably not a substantial claim. 17
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc1 and -2 ASO reduces hepatic steatosis.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
plain- Asserted: passes — The authors put it forward as true.
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- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ASO-induced inhibition of Acc2 in rat hepatocytes significantly increased fat oxidation without altering malonyl-CoA levels in tissue extracts”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effects were both isoform specific and tissue selective, and there was no apparent compensatory increase in the nontargeted isoform”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Acc ASOs also reduced ACC expression in adipose tissue (∼80%, data not shown) but not in muscle.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Overexpressing lipoprotein lipase (LPL) in the liver in mice results in fatty liver and liver-specific insulin resistance (5).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [5]
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We have also shown that moderate weight loss in humans with type 2 diabetes lowers liver TGs and specifically improves hepatic insulin sensitivity (7).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [7]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The most common disorder associated with NAFLD is insulin resistance, an association which holds true in both lean and obese subjects (3,4).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [3]
- Not checked yetcites [4]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [6]
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [8]
- Not checked yetcites [9]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They also suggest that reducing liver lipid accumulation may be an attractive therapeutic strategy for NAFLD and type 2 diabetes.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [8]
- Not checked yetcites [9]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [6]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The reduction in leptin levels during the fed state probably reflects the lower insulin levels (16).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc1 and -2 ASO reduces hepatic steatosis.
What the sources say
- Not checked yetcites [16]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“ACC2-null mice (ACC2 -/-) are leaner than wild-type controls due to increased fat oxidation in heart and skeletal muscle (12).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [12]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [12]
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“ACC1-null mice are embryonic lethal (14).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [14]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [13]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [12]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Introduction
What the sources say
- Not checked yetcites [13]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc ASOs decrease Acc expression and lower malonyl-CoA levels in rat livers.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Acc2 regulates malonyl-CoA levels in the immediate proximity of CPT1.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Acc1 and -2 ASO reduces hepatic steatosis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
What the sources say
- Not checked yetcites [14]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The adiponectin kit was primarily designed to measure mouse adiponectin, but showed significant cross-reactivity with rat adiponectin.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Biochemical analysis and calculations.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We have previously shown that this diet produces hepatic steatosis and hepatic insulin resistance within 3 days (6).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Animals.
What the sources say
- Not checked yetcites [6]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“with time a relatively modest increase in fat oxidation in the fed state results in lower liver lipid levels and improved hepatic insulin sensitivity”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“It does not have perfect complementarity to any known gene in public databases.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Selection of rat ACC ASOs.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The Yale Animal Care and Use Committee approved all protocols.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Animals.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Selection of rat ACC ASOs.
What the sources say
- Not checked yetcites [35]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It is becoming increasingly clear that hepatic lipid accumulation causes hepatic insulin resistance and contributes to the pathogenesis of type 2 diabetes (2).”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Discussion
What the sources say
- Not checked yetcites [2]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All rats were maintained in accordance with the institutional Animal Use and Care Committees of Yale University School of Medicine.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Animals.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which promotes nuclear exclusion of Foxo1, thereby lowering its transcriptional activity on the promoters of gluconeogenic genes, such as PEPCK and G6P.”
§ Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 > Statistics.
plaindirectn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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?
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
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Metadata
- 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 › Hepatology › 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.
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