Targeting peroxisomal fatty acid oxidation improves hepatic steatosis and insulin resistance in obese mice
The Journal of biological chemistry(2023)
摘要
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 floxidation is controlled by the acetyl-CoA/CoA ratio, and the acetyl-CoA generated in peroxisomal fl-oxidation could be transported into mitochondria via carnitine shuttles, we hypothesize that peroxisomal fl-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 floxidation 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 fl-oxidation. Additionally, we found that specific suppression of peroxisomal fl-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 fl-oxidation might be a promising pathway in improving hepatic steatosis and insulin resistance as induced by obesity or diabetes.
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关键词
acetyl-carnitine,fatty acid oxidation,mitochondria,obesity,peroxisomes
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