期刊
MOLECULAR CELL
卷 79, 期 1, 页码 30-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.05.007
关键词
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资金
- NIH [DK115867, DK118333]
- Washington University-Centene Corporation Personalized Medicine Initiative
- Washington University Diabetes Research Center [DK020579]
- Nutrition Obesity Research Center [DK056341]
- Children's Discovery Institute of Washington University
- St. Louis Children's Hospital [CDI-CORE-2015-505, CDI-CORE-2019-813]
- Foundation for Barnes-Jewish Hospital [3770, 4642]
- Washington University School of Medicine
- [GM103422]
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 beta-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.
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