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Review
, 59 (2), 713-23

Nonalcoholic Fatty Liver Disease, Hepatic Insulin Resistance, and Type 2 Diabetes

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Review

Nonalcoholic Fatty Liver Disease, Hepatic Insulin Resistance, and Type 2 Diabetes

Andreas L Birkenfeld et al. Hepatology.

Abstract

Nonalcoholic fatty liver disease (NAFLD), hepatic insulin resistance, and type 2 diabetes are all strongly associated and are all reaching epidemic proportions. Whether there is a causal link between NAFLD and hepatic insulin resistance is controversial. This review will discuss recent studies in both humans and animal models of NAFLD that have implicated increases in hepatic diacylglycerol (DAG) content leading to activation of novel protein kinase Cϵ (PKCϵ) resulting in decreased insulin signaling in the pathogenesis of NAFLD-associated hepatic insulin resistance and type 2 diabetes. The DAG-PKCϵ hypothesis can explain the occurrence of hepatic insulin resistance observed in most cases of NAFLD associated with obesity, lipodystrophy, and type 2 diabetes.

Conflict of interest statement

The authors have no conflict of interest to disclose

Figures

Figure 1
Figure 1. Molecular Regulation of Intrahepatic TAG and DAG Turnover
The glycerol 3-phosphate (or phosphatidic acid) pathway represents the de novo lipogenesis route in the synthesis of triglycerides (TAG) and phospholipids. Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) catalyzes the acylation of sn-glycerol-3-phosphate with acyl-coenzyme A (acyl-CoA) to generate lysophosphatidic acid (LPA), which is thought to be the rate-controlling step in TAG synthesis. PNPLA3 seems to control this step through its transacetylation property. Fatty acyl-CoAs are then successively transferred to the glycerol backbone to from diacylglycerols (catalyzed by phosphatidic acid phosphatase (PAP)) and triacylglycerols (TAG) through diacylglycerol:acyl-CoA acyltransferases (DGAT). They can also esterify with sphingosine to form ceramides. LPA and PA require translocation through the cytosol for TAG synthesis at the endoplasmic reticulum if they are not synthesized in the endoplasmic reticulum. CGI-58 controls compartmentation of DAGs. DAGs in the plasma-membrane fraction activate PKCε, which in turn attenuates insulin receptor activation through its ligand. Hydrolysis from TAG to DAG is mediated by adipose triglyceride lipase (ATGL). DAG can be further hydrolyzed to monoacylglycerol (MAG) by hormone-sensitive lipase (HSL) and subsequently to glycerol by monoglyceride lipase (MGL). These reactions release fatty acids. Glycerol can be used as a substrate for gluconeogenesis. Plasma membrane DAG stimulate PKCε membrane translocation to inhibit the insulin receptor kinase.
Figure 2
Figure 2. Mechanism of Diacylglycerol-PKCε Mediated Hepatic Insulin Resistance
Membrane-near intracellular diacyglycerols lead to activation of PKC-ε which, in turn, inhibits the insulin receptor kinase. This then leads to decreased insulin-stimulated tyrosine phosphorylation (pY) of insulin receptor substrate-1 and -2 (IRS-1, IRS-2), PI3K activation and downstream insulin signaling. The net result is a decreased in hepatic glycogen synthesis, owing to decreased activation of glycogen synthase, and increased hepatic gluconeogenesis through reduced inactivation of FOXO1, which results in an exaggerated glucose release through glucose transporter 2 (GLUT2).

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