Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cardiology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mol Cell. 2020 Jul 2;79(1):30-42.e4. doi: 10.1016/j.molcel.2020.05.007. Epub 2020 May 29.
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.
自噬在长时间禁食时被激活，但不能克服随后的肝脂质过载，导致脂肪肝。在这里，我们描述了一种过氧化物酶体 - 溶酶体代谢联系，限制了脂质的自噬降解。酰基辅酶 A 氧化酶 1（Acox1），即催化过氧化物酶体β-氧化第一步的酶，在肝脏中富集，并随着禁食或高脂肪饮食（HFD）进一步增加。肝特异性 Acox1 敲除（Acox1-LKO）小鼠由于脂滴的自噬降解诱导，防止了饥饿或 HFD 引起的肝脂肪变性。肝 Acox1 缺乏显著降低了总胞质乙酰辅酶 A 水平，导致 Raptor 乙酰化减少和 mTOR 的溶酶体定位减少，从而损害 mTORC1 的激活，mTORC1 是自噬的中央调节剂。二氯乙酸处理提高了乙酰辅酶 A 水平，恢复了 mTORC1 的激活，抑制了自噬，并增加了 Acox1-LKO 小鼠的肝甘油三酯。这些结果确定过氧化物酶体衍生的乙酰辅酶 A 是自噬的关键代谢调节剂，可控制肝脂质稳态。
