Fasting Induces Hepatic Lipid Accumulation By Stimulating Peroxisomal Dicarboxylic Acid Oxidation
JOURNAL OF BIOLOGICAL CHEMISTRY(2021)
摘要
Fasting induces lipid accumulation in the liver, while the mechanisms by which fasting dysregulates liver fatty acid oxidation are not clear. Fatty acid omega-oxidation is induced in the fasting state, and administration of dicarboxylic acids to fasting animals decreases plasma ketone bodies. We hypothesized that endogenous dicarboxylic acids might play a role in controlling mitochondrial beta-oxidation in fasting animals. A peroxisome proliferator-activated receptor-alpha agonist and an inhibitor for peroxisomal beta-oxidation were administered to the fasting rats to investigate the role of dicarboxylic acids in liver fatty acid oxidation and lipid homeostasis. We observed that excessive beta-oxidation of endogenous dicarboxylic acids by peroxisomes generated considerable levels of succinate in the liver. Excessive succinate oxidation subsequently increased the mitochondrial NADH/NAD(+) ratio and led to an accumulation of 3-OH-CoA and 2-enoyl-CoA intermediates in the liver. This further induced feedback suppression of mitochondrial beta-oxidation and promoted hepatic lipid deposition and steatosis. Specific inhibition of peroxisomal beta-oxidation attenuated fasting-induced lipid deposition in the liver by reducing succinate production and enhancing mitochondrial fatty acid oxidation. We conclude that suppression of mitochondrial beta-oxidation by oxidation of dicarboxylic acids serves as a mechanism for fasting-induced hepatic lipid accumulation and identifies cross talk between peroxisomal and mitochondrial fatty acid oxidation.
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关键词
dicarboxylic acid,fatty acid oxidation,ketogenesis,peroxisome,peroxisome proliferator activator receptor α
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