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

Eric S Goetzman,Sunder Sims-Lucas,Yuxun Zhang,Satdarshan P Monga,Xue-Jun Zhao,Steven F Dobrowolski,Sivakama S Bharathi,Kevin Peasley

doi:10.1038/s41598-020-75615-3

Abstract

Medium-chain triglycerides (MCT), containing C8–C12 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 C8/C10 fatty acids or coconut oil, which is rich in C12, for five weeks. Coconut oil, but not C8/C10 feeding, induced periportal macrovesicular steatosis in Sirt5KO mice. 14C–C12 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 C12 β-oxidation. Endoplasmic reticulum ω-oxidation, a minor fatty acid degradation pathway known to be stimulated by C12 accumulation, was increased in Sirt5KO liver. Mice lacking another mitochondrial C12 oxidation enzyme, long-chain acyl-CoA dehydrogenase (LCAD), also developed periportal macrovesicular steatosis when fed coconut oil, confirming that defective mitochondrial C12 oxidation is sufficient to induce the steatosis phenotype. Sirt5KO liver exhibited normal LCAD activity but reduced mitochondrial acyl-CoA synthetase activity with C12. 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.

Highlights

Medium-chain triglycerides (MCT), containing C8–C12 fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement
C 8, and to lesser extent C 10, can diffuse into the mitochondrial matrix where they are activated into acyl-CoAs by the medium-chain acyl-CoA synthetases (ACSMs)13. C12 cannot cross the mitochondrial membrane and is a poor substrate for A CSMs13. C12 is activated to C 12-CoA by the long-chain acyl-CoA synthetases (ACSLs), which reside on the outer mitochondrial membrane, plasma membrane, ER, and the peroxisomal membrane[14]
In hematoxylin and eosin (H&E)-stained liver sections, macrovesicular steatosis was noted only in Sirt5 knockout mice (Sirt5KO) livers from mice maintained on the coconut oil diet (Fig. 1a,b)

Summary

Introduction

Medium-chain triglycerides (MCT), containing C8–C12 fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. In H&E-stained liver sections, macrovesicular steatosis was noted only in Sirt5KO livers from mice maintained on the coconut oil diet (Fig. 1a,b). The same pattern was observed in liver homogenates prepared from mice fed coconut oil diet for five weeks (Fig. 4b,d).

Results

Conclusion