Exercise ameliorates lipid droplet metabolism disorder by the PLIN2–LIPA axis-mediated lipophagy in mouse model of non-alcoholic fatty liver disease

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-03, Vol.1870 (3), p.167045-167045, Article 167045
• Main Authors: Fang, Chunlu, Liu, Shujing, Yang, Wenqi, Zheng, Guohua, Zhou, Fu, Gao, Xiang, Qin, Lian, Yang, Guirong, Yang, Jiapei, Zhu, Guangming, Wang, Xinzhuang, Huang, Kailing, Yang, Xincheng, Wei, Yuan, Peng, Shuang, Li, Liangming
• Format: Article
• Language: English
• Subjects: Exercise; Lipid droplet; Lipophagy; Non-alcoholic fatty liver disease; PLIN2–LIPA axis
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167045

Excessive hepatic lipid droplets (LDs) accumulation-induced lipid metabolism disorder contributes to the development of non-alcoholic fatty liver disease (NAFLD). Exercise is a promising therapeutic strategy for NAFLD. However, the mechanism by which exercise ameliorates NAFLD through regulating the catabolism of hepatic LDs remains unclear. In the present study, we investigated the effect of perilipin2 (PLIN2)–lysosomal acid lipase (LIPA) axis mediating exercise-triggered lipophagy in a high-fat diet (HFD)-induced NAFLD mouse model. Our results showed that exercise could reduce HFD-induced hepatic LDs accumulation and change the expression of lipolysis-related enzymes. Moreover, exercise upregulated the expression of microtubule associated protein 1 light chain 3 (LC3) and autophagy-related proteins, and downregulated sequestosome 1 (P62) expression and promoted autophagosomes formation. Interestingly, exercise downregulated PLIN2 expression, upregulated LIPA expression, and increased the activity of hepatic LIPA and serum levels of LIPA in the NAFLD mouse model. Further mechanistic studies demonstrated that adenosine monophosphate-activated protein kinase (AMPK) activator-5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) treatment significantly increased mRNA levels and protein expression of LIPA and LC3II and decreased levels of PLIN2 and P62 in palmitic acid (PA)-treated HepG2 cells. PLIN2 silencing and LIPA overexpression notably increased the mRNA level and protein expression of LC3II and decreased the mRNA level and protein expression of p62, respectively. In summary, our findings reveal novel insights into the effect of exercise on improving lipid droplet metabolism disorder in NAFLD. Enhancing the PLIN2–LIPA axis-mediated lipophagy may be one of the key mechanisms involved in NAFLD alleviation by exercise. •Exercise enhances lipid droplets catabolism by promoting AMPKα-dependent lipophagy.•Exercise regulates lipophagy via the PLIN2-LIPA axis.•Exercise alleviates NAFLD through promoting the PLIN2-LIPA axis-mediated AMPKα-dependent lipophagy.