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Presentation transcript:

Figure 1 Pathophysiological aspects of insulin resistance in NAFLD: role of lipids and energy metabolism Figure 1 | Pathophysiological aspects of insulin resistance in NAFLD: role of lipids and energy metabolism. NAFLD is associated with hepatic and peripheral insulin resistance, resulting in an insufficient suppression of hepatic gluconeogenesis, decreased glycogen synthesis and increased lipid accumulation (1). High amounts of free fatty acids (FFA) are attributed to an increased delivery from white adipose tissue (WAT), which releases additional soluble factors such as the lipid chaperone aP2, thereby further promoting hepatic glucose metabolism. Levels of FFAs are further augmented by the availability of dietary lipids (2). De novo synthesis of FFA is driven by sterol regulatory element binding-protein 1c (SREBP-1c) and carbohydrate response element binding-protein (ChREBP) and is catalysed by hyperinsulinaemia and hyperglycaemia (3). Aggravatingly, lipid export through VLDL is decreased (4). Whereas hepatic triglycerides stored in lipid droplets can be relatively inert or even protective, FFA might substantiate insulin resistance, causing lysosomal instability with leakage of cathepsin B and induction of the NF-κB−TNFα pathway, or by activating the caspase-1−IL-1β/IL-18 pathways through the NALP3 inflammasome (5). Diacylglycerol promotes insulin resistance through the activation of protein kinase C (PKC)ε and c-Jun N-terminal kinase (JNK) (6). The hepatocyte attempts to limit FFA by increasing mitochondrial β-oxidation. Coenzyme A (CoA)-linked FFAs are shuttled into the mitochondrial matrix via carnitine O-palmitoyltransferase (CPT)1 and CPT2. Excessive acetyl-CoA is channelled into the tricarboxylic acid (TCA) cycle and NADH into the electron transport chain. Exhaustion of the antioxidant capacities of superoxide dismutase (SOD)2 and glutathione peroxidase (GPX) ultimately results in increased oxidative stress mediated by superoxide (O2−) anions, H2O2 and mitochondrial leakage, leading to aggravation of insulin resistance and progression to NASH and fibrosis (7). DGAT2, diacylglycerol O-acyltransferase 2; IRS, insulin receptor substrate. Tilg, H. et al. (2016) NAFLD and diabetes mellitus Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2016.147