Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease*

By V. Samuel, Zhen-Xiang Liu, X. Qu, B. Elder, S. Bilz, D. Befroy, Anthony J. Romanelli, Gerald I. Shulman. Journal of Biological Chemistry, 2004

1,356 citations recorded by the source corpus.

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 ∼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-ϵ 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-ϵ 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-ϵ and JNK1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase.

Subfields: Endocrinology, Diabetes and Metabolism, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7969c747e6eebd3e010ccd485b4876ab800246f2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrinology, Diabetes and Metabolism

In Epidemiology

In Molecular Biology

Citations in the corpus

SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome (2011, positive): “…and diet, multiple metabolic pathways are implicated in the pathogenesis of metabolic disease, including aberrant lipogenesis (Roden et al., 1996; Samuel et al., 2004), increased inflammation (Hotamisligil et al., 1993; Uysal et al., 1997), and reduced fatty acid oxidation (Ji and Friedman,…”
Non Alcoholic Fatty Liver Disease, Hepatic Insulin Resistance and Type 2 Diabetes (2014, background): “Hepatic steatosis and hepatic insulin resistance can be induced in mice and rats with 3 days of high-fat diet (HFD) before the development of obesity.(17) Livers of these 3-day HFD-fed rats showed increases in hepatic DAG species originating mainly from dietary sources.”
Disordered lipid metabolism and the pathogenesis of insulin resistance. (2007, neutral): “PKC- translocation to the plasma membrane and activity is increased in rats with isolated hepatic steatosis and hepatic insulin resistance following 3 days of high fat feeding (96), suggesting that PKC- may be an important mediator of fatinduced insulin resistance in liver.”
Hepatocyte-specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation (2009, background): “Dysregulation of lipid metabolic pathways results in the development of hepatic steatosis and contributes to the development of chronic hepatic inflammation, insulin resistance, and liver damage (Browning and Horton, 2004; Samuel et al., 2004; Sanyal, 2005).”
Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. (2005, background): “These changes were associated with increases in hepatic fatty acyl CoAs, reduced insulin activation of IRS-1– and IRS-2–associated phosphatidylinositol 3-kinase, activation of protein kinase C , and increased gluconeogenesis (10).”
Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet (2012, neutral): “Voluntary energy intake is often independent of dietary fat content both in rodents and in human twins (examples include but are not limited to Bray et al., 2010; Fujisaka et al., 2011; Hosooka et al., 2008; Kennedy et al., 2007; Lin et al., 2000; Saltzman et al., 1997; Samuel et al., 2004), and the”
NAFLD: a multisystem disease. (2015, background): “In NAFLD, secretion of diabetogenic hepatokines, such as retinol binding protein (RBP)-4, fetuin-A, fibroblast growth factor (FGF)-21; or inflammatory biomarkers such as C-reactive protein (CRP), TNF-a and IL-6 [73] may directly affect risk of incident T2DM by adversely affecting hepatic gluconeogen”
Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction (2006, background): “Increased gluconeogenesis further exacerbates hepatic insulin resistance and results in fasting hyperglycemia (43,75,76).”
IKK-β links inflammation to obesity-induced insulin resistance (2005, background): “Indeed, lipid accumulation in liver is a hallmark of HFD-induced insulin resistanc”
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. (2005, positive): “Western blotting was performed as described previously (36).”