The lysine desuccinylase SIRT5 regulates hepatic metabolism of medium-chain fatty acids

Presented By:

Eric S Goetzman*, Sivakama Bharathi, Yuxun Zhang, Xuejun Zhao, Kevin Peasley, Steven Dobrowolski, Sunder Sims-Lucas, and Satdarshan Monga

University of Pittsburgh, Pittsburgh, PA United States

*Corresponding author: eric.goetzman@chp.edu, 412-692-7952

BACKGROUND: Sirtuin-5 (Sirt5) is a lysine deacylase enzyme that removes post-translational modifications from mitochondrial, cytosolic, and peroxisomal proteins. Medium-chain fatty acid (MCFA) are prevalent in coconut oil and medium-chain triglyceride (MCT) oil.

METHODS: Sirt5-/- mice were fed diets rich in long-chain triglycerides (LCT), MCT, or coconut oil for five weeks. Liver was evaluated by histology, enzyme activity assays, western blotting, and triglyceride assays. Urine organic acids were measured by GC-MS. FAO was determined with radiolabeled tracers.

RESULTS: Sirt5-/- mice developed an unusual pattern of periportally-zoned macrovesicular steatosis on the coconut oil and MCT, but not LCT, diets. Oxidation of 14C-lauric acid was significantly lower in Sirt5-/- liver. Long-chain acyl-CoA dehydrogenase knockout mice showed the same periportal steatosis as Sirt5-/- mice on coconut oil, but activity of the acyl-CoA dehydrogenases was normal in Sirt5-/- liver. Immunohistochemistry and western blotting showed that peroxisomes were recruited into the periportal zone in livers from Sirt5-/- mice fed coconut oil, and urinary adipic acid increased 16-fold over wild-type. Inhibition of peroxisomal FAO with 10,12-tricosadiynoic acid exacerbated the steatosis and triglyceride accumulation in livers of Sirt5-/- mice fed coconut oil but had no effect in wild-type mice.

DISCUSSION: Mitochondrial FAO in the periportal zone is required for metabolism of MCFA. Peroxisomal recruitment is not sufficient to prevent fat accumulation. Sirt5-/- mice have reduced mitochondrial MCFA oxidation, but the defect is not at the level of the acyl-CoA dehydrogenases. Further studies are underway to determine which step of medium-chain FAO is impaired in Sirt5-/- liver. Sirt5-/- mice fed MCFA may be a useful model to study human pediatric fatty liver disease, in which macrovesicular steatosis occurs in the periportal region rather than the pericentral region as seen in adults.