Targeting peroxisomal fatty acid oxidation improves hepatic steatosis and insulin resistance in obese mice.

Content Provider	Europe PMC
Author	Yao, Haoya Wang, Yaoqing Zhang, Xiao Li, Ping Shang, Lin Chen, Xiaocui Zeng, Jia
Copyright Year	2022
Abstract	Obesity and diabetes normally cause mitochondrial dysfunction and hepatic lipid accumulation, while fatty acid synthesis is suppressed and malonyl-CoA is depleted in the liver of severe obese or diabetic animals. Therefore, a negative regulatory mechanism might work for the control of mitochondrial fatty acid metabolism that is independent of malonyl-CoA in the diabetic animals. As mitochondrial β-oxidation is controlled by the acetyl-CoA/CoA ratio, and the acetyl-CoA generated in peroxisomal β-oxidation could be transported into mitochondria via carnitine shuttles, we hypothesize that peroxisomal β-oxidation might play a role in regulating mitochondrial fatty acid oxidation and inducing hepatic steatosis under the condition of obesity or diabetes. This study reveals a novel mechanism by which peroxisomal β-oxidation controls mitochondrial fatty acid oxidation in diabetic animals. We determined that excessive oxidation of fatty acids by peroxisomes generates considerable acetyl-carnitine in the liver of diabetic mice, which significantly elevates the mitochondrial acetyl-CoA/CoA ratio and causes feedback suppression of mitochondrial β-oxidation. Additionally, we found that specific suppression of peroxisomal β-oxidation enhances mitochondrial fatty acid oxidation by reducing acetyl-carnitine formation in the liver of obese mice. In conclusion, we suggest that induction of peroxisomal fatty acid oxidation serves as a mechanism for diabetes-induced hepatic lipid accumulation. Targeting peroxisomal β-oxidation might be a promising pathway in improving hepatic steatosis and insulin resistance as induced by obesity or diabetes.
ISSN	00219258
Volume Number	299
PubMed Central reference number	PMC9898756
Issue Number	2
PubMed reference number	36586435
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2022.102845
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2022-12-28
Access Restriction	Open
Rights License	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). © 2022 The Authors
Subject Keyword	fatty acid oxidation peroxisomes mitochondria acetyl-carnitine obesity ACD, acyl-CoA dehydrogenase CAT, carnitine acetyltransferase FAO, fatty acid oxidation HOMA-IR, homeostasis model assessment of insulin resistance IR, insulin resistance LCACD, long-chain acyl-CoA dehydrogenase LC-CoA, long-chain acyl-CoA MCACD, medium-chain acyl-CoA dehydrogenase TAG, triacylglyceride TDYA, 10,12-tricosadiynoic acid
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry