212-OR: Hepatic Overexpression of ACSS3 Alters Glucose Control and Fatty Acid Metabolism in Lean Mice
SESHADRI, N; MUOIO, DM; WILLIAMS, AS
Published in: Diabetes
Introduction and Objective: Short chain fatty acids (SCFAs) are associated with adverse metabolic outcomes; however, little is known about their link to metabolic disease. Emerging evidence suggests that in addition to acting as signaling molecules, SCFAs also impact cellular metabolism via their conversion to acyl-CoAs by short chain acyl-CoA synthetase (ACSS) enzymes. ACSS3 is a mitochondrial enzyme highly expressed in liver; and recent studies from our laboratory using mass-spectrometry (MS)-based proteomics identified ACSS3 as the most downregulated protein in liver mitochondria from mice adapted to time-restricted feeding. Conversely, high fat feeding led to a marked increase in hepatic ACSS3. In this study, we sought to determine if overexpression (OE) of ACSS3 in hepatocytes of lean mice would be sufficient to mimic the metabolic effects of a high fat diet.Methods: Chow fed C57BL/6NJ mice were injected with AAV8-TBG-ACSS3 or AAV8-TBG-eGFP and metabolic phenotyping was performed along with MS-based metabolomic profiling.Results: Injection of AAV8-TBG-ACSS3 increased ACSS3 expression and activity in liver mitochondria while also elevating fasting blood glucose levels, but without affecting glucose tolerance. MS-based metabolite profiling of liver tissue showed that ACSS3 OE increased numerous acyl-CoA species, decreased free CoA, altered several short chain acylcarnitines, and led to a marked accumulation of fatty acid-derived acylcarnitines. These results suggest that increased flux through ACSS3 can contribute to mitochondrial CoA trapping, which may limit fatty acid oxidation and promote hepatic lipid accumulation. Studies to further investigate the impact of ACSS3 OE on hepatic fatty acid oxidation and steatosis are ongoing.Conclusion: In sum, our results demonstrate that hepatic ACSS3 is nutritionally regulated and OE of the enzyme altered short chain carbon trafficking in a manner that influenced whole-body glucose control and hepatic lipid metabolism.
