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Review
. 2014 Jun 5;510(7503):84-91.
doi: 10.1038/nature13478.

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Rachel J Perry  1 , Varman T Samuel  2 , Kitt F Petersen  3 , Gerald I Shulman  4
Affiliations
Review

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Rachel J Perry et al. Nature. .

Abstract

Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Molecular mechanism by which excess diacylglycerol leads to hepatic insulin resistance and hyperglycaemia
Increases in liver diacylglycerol (DAG) cause protein kinase Cε (PKCε) activation and translocation to the cell membrane, which results in inhibition of insulin signalling. Reduced phosphorylation of insulin receptor substrate-2 (IRS2) and PI(3)K impairs Akt2 activity by reductions in 3-phosphoinositide-dependent protein kinase 1 (PDK1) activity, suppressing glycogen synthase kinase-3 (GSK3) phosphorylation and reducing insulin-stimulated liver glycogen synthesis through reduced glycogen synthase (GS) activity. Impaired Akt2 activity also reduces insulin suppression of hepatic gluconeogenesis by promoting Forkhead box protein O1 (FOXO1) translocation to the nucleus due to reduced phosphorylation and increasing expression of the gluconeogenic proteins pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase). PIP3, phosphatidylinositol (3,4,5)-triphosphate.
Figure 2
Figure 2. NAFLD develops due to an imbalance between lipid supply and demand
Fatty acids (FAs) derived from lipolysis and from chylomicron remnants are taken up through fatty-acid transport proteins (FATPs), mainly FATP2 and FATP5 in the liver; chylomicron remnants are also taken up through the low-density lipoprotein (LDL) receptor. A small fraction of intracellular fatty acid supply in the liver also comes from de novo lipogenesis in the cytosol. Fatty acids can also be re-esterified to lysophosphatidic acid (LPA) by acyl-coenzyme A (AcCoA) and the conversion of glycerol 3-phosphate (G3P) by either mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT) or microsomal GPAT (msGPAT). Fatty-acyl CoAs (shown here as phosphatidic acid, PA) formed by 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2) are then added to the glycerol backbone by phosphatidic acid phosphatase (PAP) to generate diacylglycerol (DAG), and by diacylglycerol acyltransferases (DGAT) to generate triacylglycerol (TAG). Increased DAG causes protein kinase Cε (PKCε) translocation to the cell membrane, which inhibits insulin signalling. Lipids may also be sequestered in lipid droplets as monoacylglycerol (MAG), DAG and TAG, but these are not thought to be responsible for hepatic insulin resistance. By inhibition of adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58) bound to perilipin is mainly responsible for lipid sequestration in the droplet. By contrast, intracellular hepatic lipid content is reduced by two mechanisms: mitochondrial fatty acid oxidation and export from the smooth endoplasmic reticulum (SER) as very-low-density lipoprotein (VLDL). HSL, hormone-sensitive lipase; MTTP, microsomal triglyceride transfer protein.
Figure 3
Figure 3. Mechanism by which selective skeletal muscle insulin resistance contributes to hepatic insulin resistance
In insulin-sensitive subjects, insulin stimulates glycogen synthesis in both liver and muscle; however, in those with skeletal muscle insulin resistance, insulin fails to promote glycogen synthesis, diverting substrate to de novo lipogenesis. Increased lipid synthesis in patients with muscle insulin resistance thus produces non-alcoholic fatty liver disease (NAFLD), with increased triglyceride and reduced high-density lipoprotein (HDL) export from the liver. However, these defects in muscle insulin signalling can be reversed by a single 45 minute bout of exercise.
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