Acetyl-CoA Derived from Hepatic Peroxisomal β-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation

Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step i...

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Veröffentlicht in:Molecular cell 2020-07, Vol.79 (1), p.30-42.e4
Hauptverfasser: He, Anyuan, Chen, Xiaowen, Tan, Min, Chen, Yali, Lu, Dongliang, Zhang, Xiangyu, Dean, John M., Razani, Babak, Lodhi, Irfan J.
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Sprache:eng
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Zusammenfassung:Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step in peroxisomal β-oxidation, is enriched in liver and further increases with fasting or high-fat diet (HFD). Liver-specific Acox1 knockout (Acox1-LKO) protected mice against hepatic steatosis caused by starvation or HFD due to induction of autophagic degradation of lipid droplets. Hepatic Acox1 deficiency markedly lowered total cytosolic acetyl-CoA levels, which led to decreased Raptor acetylation and reduced lysosomal localization of mTOR, resulting in impaired activation of mTORC1, a central regulator of autophagy. Dichloroacetic acid treatment elevated acetyl-CoA levels, restored mTORC1 activation, inhibited autophagy, and increased hepatic triglycerides in Acox1-LKO mice. These results identify peroxisome-derived acetyl-CoA as a key metabolic regulator of autophagy that controls hepatic lipid homeostasis. [Display omitted] •Fasting or high-fat diet increases the liver gene expression of Acox1•Acox1-LKO mice are protected against fatty liver through induction of lipophagy•Acetyl-CoA from Acox1-mediated β-oxidation activates mTORC1 and inhibits lipophagy•Pharmacologically increasing acetyl-CoA rescues the phenotype in Acox1-LKO mice Autophagy is activated by starvation but is not sufficient to prevent the resulting fatty liver. He et al. describe a peroxisome-lysosome crosstalk that restricts autophagic degradation of lipid droplets in the fasted state. They show that acetyl-CoA derived from peroxisomal β-oxidation inhibits lipophagy by promoting Raptor acetylation and mTORC1 activation.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2020.05.007