Long-chain dicarboxylic acids play a critical role in inducing peroxisomal -oxidation and hepatic triacylglycerol accumulation
The Journal of biological chemistry(2023)
Abstract
Recent studies provide evidence that peroxisomal II -oxidation negatively regulates mitochondrial fatty acid oxidation, and induction of peroxisomal II -oxidation causes hepatic lipid accumulation. However, whether there exists a triggering mechanism inducing peroxisomal II -oxidation is not clear. Long -chain dicarboxylic acids (LCDAs) are the product of mono fatty acids subjected to w -oxidation, and both fatty acid w -oxidation and peroxisomal II -oxidation are induced under ketogenic conditions, indicating there might be a crosstalk between. Here, we revealed that administration of LCDAs strongly induces peroxisomal fatty acid II -oxidation and causes hepatic steatosis in mice through the metabolites acetyl-CoA and hydrogen peroxide. Under ketogenic conditions, upregulation of fatty acid w -oxidation resulted in increased generation of LCDAs and induction of peroxisomal II -oxidation, which causes hepatic accumulation of lipid droplets in animals. Inhibition of fatty acid w -oxidation reduced LCDA formation and significantly lowered peroxisomal II -oxidation and improved hepatic steatosis. Our results suggest that endogenous LCDAs act as triggering molecules inducing peroxisomal II -oxidation and hepatic triacylglycerol deposition. Targeting fatty acid woxidation might be an effective pathway in treating fatty liver and related metabolic diseases through regulating peroxisomal II -oxidation.
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Key words
dicarboxylic acids,ω-oxidation,peroxisomes,mitochondria,hepatic steatosis
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