期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 14, 页码 5631-5646出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-03869-9
关键词
Multi-functional enzyme 1; LBP; Fatty acid oxidation; Omega-oxidation; Dodecanedioic acid; Hexadecanedioic acid
资金
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [R01DK113172]
Peroxisomes play a crucial role in the beta-oxidation of dicarboxylic acids, with deficiency of the bifunctional protein EHHADH leading to medium-chain 3-hydroxydicarboxylic aciduria. The products of DCA metabolism can be transported to mitochondria for further metabolism through stable isotope tracing methodology.
Peroxisomes play an essential role in the beta-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon omega-oxidation of fatty acids. Genetic evidence linking transporters and enzymes to specific DCA beta-oxidation steps is generally lacking. Moreover, the physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to characterize the DCA beta-oxidation pathway in human cells, and to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal l-bifunctional protein (Ehhadh KO mice). In vitro experiments using HEK-293 KO cell lines demonstrate that ABCD3 and ACOX1 are essential in DCA beta-oxidation, whereas both the bifunctional proteins (EHHADH and HSD17B4) and the thiolases (ACAA1 and SCPx) have overlapping functions and their contribution may depend on expression level. We also show that medium-chain 3-hydroxydicarboxylic aciduria is a prominent feature of EHHADH deficiency in mice most notably upon inhibition of mitochondrial fatty acid oxidation. Using stable isotope tracing methodology, we confirmed that products of peroxisomal DCA beta-oxidation can be transported to mitochondria for further metabolism. Finally, we show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA beta-oxidation is a regulator of hepatic cholesterol biosynthesis.
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