Sen Sandhya, Weller Shaun, Schulze Ryan J, Ding Donglin, Casey Carol A, Weihl Conrad, McNiven Mark A
The GI Center for Digestive Diseases, The Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
The Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
J Cell Biol. 2025 Aug 4;224(8). doi: 10.1083/jcb.202408205. Epub 2025 Jul 29.
The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17β13) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor MG132 had no effect on HSD17β13 levels, while a disruption of lysosome function and chaperone-mediated autophagy increased cellular HSD17β13 levels substantially. These findings provide new insights into the cellular mechanisms by which the liver regulates its lipid stores and how this is disrupted by chronic EtOH exposure.
肝脏储存着大量被称为脂滴（LDs）的中性脂质细胞器，这些脂滴在肝细胞内积累，是对慢性乙醇（EtOH）摄入的反应，会导致肝脏脂肪变性。对从乙醇损伤的大鼠肝脏中分离出的脂滴进行质谱分析发现，含缬酪肽蛋白ATP酶（VCP/p97）显著减少，该酶的作用是从细胞膜上清除靶向蛋白质以进行降解。实验性破坏VCP功能导致肝细胞和小鼠肝脏中脂滴含量增加，同时已知会导致肝脏脂肪变性的与脂滴相关的羟类固醇脱氢酶（HSD17β13）显著增加。令人惊讶的是，用蛋白酶体抑制剂MG132处理肝细胞对HSD17β13水平没有影响，而破坏溶酶体功能和伴侣介导的自噬会使细胞内HSD17β13水平大幅增加。这些发现为肝脏调节其脂质储存的细胞机制以及慢性乙醇暴露如何破坏这一机制提供了新的见解。
