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.