Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
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Short term high fat feeding in rats results specifically in hepatic fat accumulation and provides a model of non-alcoholic fatty liver disease in which to study the mechanism of hepatic insulin resistance. Short term fat feeding (FF) caused a approximately 3-fold increase in liver triglyceride and total fatty acyl-CoA content without any significant increase in visceral or skeletal muscle fat content. Suppression of endogenous glucose production (EGP) by insulin was diminished in the FF group, despite normal basal EGP and insulin-stimulated peripheral glucose disposal. Hepatic insulin resistance could be attributed to impaired insulin-stimulated IRS-1 and IRS-2 tyrosine phosphorylation. These changes were associated with activation of PKC-epsilon and JNK1. Ultimately, hepatic fat accumulation decreased insulin activation of glycogen synthase and increased gluconeogenesis. Treatment of the FF group with low dose 2,4-dinitrophenol to increase energy expenditure abrogated the development of fatty liver, hepatic insulin resistance, activation of PKC-epsilon and JNK1, and defects in insulin signaling. In conclusion, these data support the hypothesis hepatic steatosis leads to hepatic insulin resistance by stimulating gluconeogenesis and activating PKC-epsilon and JNK1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase.
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The standard HFD induces insulin resistance systemically and in the liver but does not induce NASH.
“utilizing the standard HFD that induces insulin resistance systemically and in the liver 60 but does not induce NASH 61”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [60]
Wild-type mice and rats develop hepatic steatosis after a few days of high-fat feeding that is associated with hepatic insulin resistance, without much change in muscle lipid content or peripheral insulin action.
“Wild-type mice and rats develop hepatic steatosis after a few days of high-fat feeding that is associated with hepatic insulin resistance, without much change in muscle lipid content or peripheral insulin action.100”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [100]
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 [21]
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 [21]
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 [23]
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 [23]
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 [10]
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 [10]
Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance.
“Three days of high-fat feeding in rats results specifically in hepatic steatosis and hepatic insulin resistance.”
From Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease (2007) · cites this paper as [10]
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 [10]
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 [21]
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BackgroundInfluentialThe Oxygen Paradox, the French Paradox, and age-related diseases
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Self-citation
- Authors
- Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I.
- Affiliations
- Yale University (US)
- University of Technology Sydney (AU)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 279
- Issue
- 31
- Pages
- 32345-32353
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2012295774
- Cited by
- 1,322
- References
- 30
- Citations by year
- 2026: 31 · 2025: 33 · 2024: 38 · 2023: 29 · 2022: 39 · 2021: 58 · 2020: 57 · 2019: 69 · 2018: 67 · 2017: 66 · 2016: 81 · 2015: 70 · 2014: 65 · 2013: 77 · 2012: 82
- FWCI
- 39.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UTS ePRESS (University of Technology Sydney) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, P30DK045735)
- National Center for Research Resources (K23RR017404, K23 RR-17404)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- hepatic insulin resistance, non-alcoholic fatty liver disease, hepatic steatosis, high-fat feeding, endogenous glucose production, IRS-1 tyrosine phosphorylation, protein kinase C epsilon, JNK1, glycogen synthase, gluconeogenesis, 2,4-dinitrophenol, energy expenditure, insulin signaling, hepatic triglycerides, fatty acyl-CoA
- MeSH terms
- Animals, Cell Membrane, Cytosol, Deoxyglucose, Enzyme Activation, Fatty Acids, Fatty Liver, Glycogen, Glycogen Synthase, Insulin, Insulin Resistance, Liver, Male, Phosphorylation, Precipitin Tests, Protein Kinase C, RNA, Messenger, Time Factors, Tyrosine, Blotting, Western, Signal Transduction, Rats, Sprague-Dawley, Protein Isoforms, Mitogen-Activated Protein Kinases, Protein Transport, Mitogen-Activated Protein Kinase 8, Lipid Metabolism, Rats, Protein Kinase C-epsilon
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