Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice.

Medium-chain triglycerides (MCT), containing C-C fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. Here, we investigated the role of the sirtuin deacylase Sirt5 in MCT metabolism by feeding Sirt5 knockout mice (Sirt5KO) high-fat diets containing either C/C fatty acids or coconut oil, which is rich in C, for five weeks. Coconut oil, but not C/C feeding, induced periportal macrovesicular steatosis in Sirt5KO mice. C-C degradation was significantly reduced in Sirt5KO liver. This decrease was localized to the mitochondrial β-oxidation pathway, as Sirt5KO mice exhibited no change in peroxisomal C β-oxidation. Endoplasmic reticulum ω-oxidation, a minor fatty acid degradation pathway known to be stimulated by C accumulation, was increased in Sirt5KO liver. Mice lacking another mitochondrial C oxidation enzyme, long-chain acyl-CoA dehydrogenase (LCAD), also developed periportal macrovesicular steatosis when fed coconut oil, confirming that defective mitochondrial C oxidation is sufficient to induce the steatosis phenotype. Sirt5KO liver exhibited normal LCAD activity but reduced mitochondrial acyl-CoA synthetase activity with C. These studies reveal a role for Sirt5 in regulating the hepatic response to MCT and may shed light into the pathogenesis of periportal steatosis, a hallmark of human pediatric non-alcoholic fatty liver disease.