BACKGROUND & AIMS: The risk of non-alcoholic fatty liver disease (NAFLD) exhibits large inter-individual variability. Part of it is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contributes to the pathogenesis of NAFLD. METHODS: We studied 846 individuals of whom 492 were obese patients with liver histology, and 354 subjects who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFA) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n=41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n=61). RESULTS: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFA and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. CONCLUSIONS: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to diagnosis and treatment targets of NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Here, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
HSD17B13, MARC1, MBOAT7, PNPLA3, TM6SF2, adipose tissue lipolysis, de novo lipogenesis, hepatic mitochondrial redox state, insulin resistance, metabolomics