Investigating the Role of NUDT7-mediated Peroxisomal CoA Degradation in the Regulation of Hepatic CoA Levels and Lipid Metabolism

Coenzyme A (CoA) is a crucial cofactor required to support many essential metabolic processes, including fatty acid oxidation and synthesis, the TCA cycle, and bile acid synthesis. In order to support the proper functioning of these pathways, CoA levels within the cell must be properly regulated. The regulation of CoA levels is achieved through a balance between CoA synthesis and CoA degradation. While the regulation of CoA synthesis has been extensively characterized, the degradation of CoA has received less attention. As such, the contribution of CoA degradation to the regulation of metabolism is poorly understood. NUDT7 is a CoA-specific Nudix hydrolase highly expressed in the liver and localized to the peroxisomes. This enzyme has been shown to degrade free CoA and a range of acyl-CoA species, including the CoA derivatives of bile acids. Liver-specific over-expression of NUDT7 resulted in selective decreases in peroxisomal fatty acid oxidation and hepatic bile acid levels. Other investigations into the consequences of NUDT7 deficiency have implicated a role for this enzyme in the regulation of the development of several pathological conditions including osteoarthritis, colorectal cancer, and nonalcoholic steatohepatitis. Herein, we investigated the effect of Nudt7 deletion on hepatic lipid metabolism in mice. We observed that in male mice fed a high fat, high cholesterol diet, Nudt7 deletion increased total hepatic CoA levels and changed the composition of the intestinal bile acid pool. The compositional changes decreased the overall hydrophobicity index of the intestinal bile acid pool and interfered with the ability of the Nudt7-/- mice to absorb dietary cholesterol. This work provides insight into the in vivo role of NUDT7 in the regulation of hepatic CoA levels and lipid metabolism