Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an essential role in lipid metabolism, yet their importance is often overlooked. In a recent study, we demonstrated a role for hepatic peroxisomal β-oxidation in autophagic degradation of lipid droplets. ACOX1 (acyl-Coenzyme A oxidase 1, palmitoyl), the rate-limiting enzyme of peroxisomal β-oxidation, increases with fasting or high-fat diet (HFD). Liver-specific acox1 knockout (acox1-LKO) protects mice from hepatic steatosis induced by starvation or HFD via induction of lipophagy. Mechanistically, we showed that hepatic ACOX1 deficiency decreases the total cytosolic acetyl-CoA levels, which leads to reduced acetylation of RPTOR/RAPTOR, a component of MTORC1, which is a key regulator of macroautophagy/autophagy. These results identify peroxisome-derived acetyl-CoA as a critical metabolic regulator of autophagy that controls hepatic lipid homeostasis.

肝脏脂质稳态受各种代谢途径的协调调节控制，这些代谢途径涉及脂质的从头合成、摄取、储存和分解代谢。这种平衡的破坏可能导致肝脂肪变性。过氧化物酶体在脂质代谢中起重要作用，但它们的重要性经常被忽视。在最近的一项研究中，我们证明了肝脏过氧化物酶体 β-氧化在脂滴自噬降解中的作用。ACOX1（酰基辅酶 A 氧化酶 1，棕榈酰）是过氧化物酶体 β-氧化的限速酶，随着禁食或高脂肪饮食 (HFD) 增加。肝脏特异性acox1敲除 ( acox1-LKO) 通过诱导脂肪吞噬保护小鼠免受饥饿或 HFD 诱导的肝脂肪变性。从机制上讲，我们发现肝脏 ACOX1 缺乏会降低总细胞溶质乙酰辅酶 A 水平，这导致 RPTOR/RAPTOR（MTORC1 的一个组成部分）的乙酰化降低，MTORC1 是巨自噬/自噬的关键调节剂。这些结果表明，过氧化物酶体衍生的乙酰辅酶 A 是控制肝脏脂质稳态的自噬的关键代谢调节剂。