Perilipin 5 regulates hepatic stellate cell activation and high-fat diet-induced non-alcoholic fatty liver disease

Background: Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. Hepatic stellate cells (HSCs) are major effectors of liver fibrosis and contain abundant lipid droplets (LDs) in quiescence. Perilipin 5 (PLIN5), a LD surface-associated protein, is key in lipid homeostasis, but its role in HSC activation is unclear. Methods: PLIN5 was overexpressed in rat HSCs via lentiviral transduction. PLIN5 knockout (PLIN5−/−) mice were generated and fed a high-fat diet (HFD) for 20 weeks to evaluate PLIN5 in NAFLD. Triglycerides (TG), reduced glutathione (GSH), caspase-3 activity, ATP levels, and mitochondrial DNA copy number were measured with commercial kits. Untargeted liver metabolomics used UPLC-MS/MS. AMPK activation, mitochondrial function, proliferation, and apoptosis-related genes/proteins were assessed by western blot and qPCR. Results: PLIN5 overexpression in activated HSCs decreased mitochondrial ATP, inhibited proliferation, and increased apoptosis via AMPK activation. In vivo, compared with HFD-fed C57BL/6J mice, HFD-fed PLIN5−/− mice exhibited reduced hepatic fat deposition, decreased LD abundance and size, and attenuated liver fibrosis. Conclusion: These findings highlight a regulatory role of PLIN5 in HSC activation and implicate PLIN5 in the fibrosis process of NAFLD.

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