Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. Hepatic stellate cells (HSCs), key players in liver fibrosis, contain abundant lipid droplets (LDs). Perilipin 5 (PLIN5), an LD surface protein, is crucial for lipid homeostasis. This study investigated PLIN5's role in HSC activation and NAFLD. PLIN5 overexpression in HSCs decreased mitochondrial ATP levels, inhibited proliferation, and increased apoptosis via AMPK activation. PLIN5 knockout mice fed a high-fat diet (HFD) showed reduced liver fat deposition, fibrosis, and improved glucose homeostasis. Metabolomic analysis revealed alterations in glutamate and glutathione metabolism. PLIN5 deletion suppressed HFD-induced mitochondrial dysfunction and apoptosis through the AMPK/PGC1α pathway.

Xuecui Yin, Lin Dong, Xiaohan Wang, Zhenzhen Qin, Yuying Ma, Xiaofei Ke, Ya Li, Qingde Wang, Yang Mi, Quanjun Lyu, Xia Xu, Pengyuan Zheng, Youcai Tang