Abstract
Lipid metabolism requires CoA, an essential cofactor found in multiple subcellular compartments, including the peroxisomes. In the liver, CoA levels are dynamically adjusted between the fed and fasted states. Elevated CoA levels in the fasted state are driven by increased synthesis; however, this also correlates with decreased expression of Nudix hydrolase (Nudt)7, the major CoA-degrading enzyme in the liver. Nudt7 resides in the peroxisomes, and we overexpressed this enzyme in mouse livers to determine its effect on the size and composition of the hepatic CoA pool in the fed and fasted states. Nudt7 overexpression did not change total CoA levels, but decreased the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, when endogenous Nudt7 activity was lowest. The effect on these acyl-CoAs correlated with a significant decrease in the hepatic bile acid content and in the rate of peroxisomal fatty acid oxidation, as estimated by targeted and untargeted metabolomics, combined with the measurement of fatty acid oxidation in intact hepatocytes. Identification of the CoA species and metabolic pathways affected by the overexpression on Nudt7 in vivo supports the conclusion that the nutritionally driven modulation of Nudt7 activity could contribute to the regulation of the peroxisomal CoA pool and peroxisomal lipid metabolism.
Highlights
Lipid metabolism requires CoA, an essential cofactor found in multiple subcellular compartments, including the peroxisomes
Overexpression of Nudt7 does not prevent the increase in total CoA levels that occurs in fasted livers
We found that CoA levels increased significantly after a 12 h fast (Fig. 1A) and plateaued after a 24 h fast, closely matching the time course of the decrease in Nudt7 mRNA (Fig. 1B) and CoA-degrading activity (Fig. 1C) in the liver
Summary
Lipid metabolism requires CoA, an essential cofactor found in multiple subcellular compartments, including the peroxisomes. Free CoA and acyl-CoAs support specific pathways and reactions These include ketogenesis, the TCA cycle, fatty acid -oxidation in the mitochondria, fatty acid synthesis in the cytosol, autophagy in the endoplasmic reticulum, and the last steps in the bile acid biosynthetic pathway and fatty acid - and -oxidation in the peroxisomes [3, 12, 14]. CoA levels change in response to the nutritional state to support the switch between glucose and fatty acid oxidation [11, 15, 16] This dynamic modulation occurs through a balance between CoA synthesis and degradation, which leads to a net increase in the concentration of hepatic CoA in the fasted state and to a net decrease in the fed state [16,17,18].
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