Acot9 traffics mitochondrial short-chain fatty acids towards de novo lipogenesis and glucose production in the liver

Obesity-induced pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is associated with increased de novo lipogenesis (DNL) and hepatic glucose production (HGP) due to excess fatty acids. Acyl-CoA thioesterase (Acot) family members control the cellular utilization of fatty acids by hydrolyzing (deactivating) acyl-CoA into non-esterified fatty acids and CoASH. Using C. elegans, we identified Acot9 as the strongest regulator of lipid accumulation within Acot family. Indicative of a maladaptive function, hepatic Acot9 expression was higher in obese patients with NAFLD and NASH compared to healthy obese controls. In the setting of excessive nutrition, global ablation of Acot9 protected mice against increases in weight gain, HGP, steatosis and steatohepatitis. Supportive of a hepatic function, the liver-specific deletion of Acot9 inhibited HGP and steatosis in mice without affecting diet-induced weight gain. By contrast, the rescue of Acot9 expression only in the livers of Acot9 knockout mice was sufficient to promote HGP and steatosis. Mechanistically, hepatic Acot9 localized to the inner mitochondrial membrane where it deactivated short-chain but not long-chain fatty acyl-CoA. This unique localization and activity of Acot9 directed acetyl-CoA away from protein lysine acetylation and towards the citric acid (TCA) cycle. Acot9-mediated exacerbation of triglyceride and glucose biosynthesis was attributable at least in part to increased TCA cycle activity, which provided substrates for HGP and DNL. β-oxidation and ketone body production, which depend on long-chain fatty acyl-CoA were not regulated by Acot9. Taken together, our findings indicate that Acot9 channels hepatic acyl-CoAs towards increased HGP and DNL under the pathophysiology of obesity. Therefore, Acot9 represents a novel target for the management of NAFLD.