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.

长时间禁食会激活自噬，但无法克服随之而来的肝脏脂质超载，从而导致脂肪肝。在这里，我们描述了限制脂质自噬降解的过氧化物酶体-溶酶体代谢联系。酰基辅酶 A 氧化酶 1 (Acox1) 是催化过氧化物酶体 β-氧化第一步的酶，在肝脏中富集，并随着禁食或高脂饮食 (HFD) 进一步增加。肝脏特异性 Acox1 敲除 (Acox1-LKO) 保护小鼠免受饥饿或 HFD 引起的脂肪变性，这是由于脂滴自噬降解的诱导。肝脏 Acox1 缺陷显着降低了总细胞溶质乙酰辅酶 A 水平，这导致 Raptor 乙酰化减少和 mTOR 溶酶体定位减少，导致自噬中央调节因子 mTORC1 的激活受损。二氯乙酸处理提高了 Acox1-LKO 小鼠的乙酰辅酶 A 水平，恢复了 mTORC1 激活，抑制了自噬，并增加了肝脏甘油三酯。这些结果将过氧化物酶体衍生的乙酰辅酶 A 确定为控制肝脏脂质稳态的自噬的关键代谢调节剂。