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

Chunlu Fang; Shujing Liu; Wenqi Yang; Guohua Zheng; Fu Zhou; Xiang Gao; Lian Qin; Guirong Yang; Jiapei Yang; Guangming Zhu; Xinzhuang Wang; Kailing Huang; Xincheng Yang; Yuan Wei; Shuang Peng; Liangming Li

doi:10.1016/j.bbadis.2024.167045

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

Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167045. doi: 10.1016/j.bbadis.2024.167045. Epub 2024 Feb 2.

Authors

Chunlu Fang¹, Shujing Liu¹, Wenqi Yang¹, Guohua Zheng², Fu Zhou³, Xiang Gao⁴, Lian Qin³, Guirong Yang³, Jiapei Yang³, Guangming Zhu³, Xinzhuang Wang³, Kailing Huang³, Xincheng Yang³, Yuan Wei⁵, Shuang Peng⁶, Liangming Li⁷

Affiliations

¹ School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China; Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, China.
² Institute of leisure, Shanghai University of Sport, Shanghai 200438, China.
³ Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, China.
⁴ Sports Training Institute, Guangzhou Sport University, Guangzhou 510500, China.
⁵ Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, China. Electronic address: weiyuan0808@163.com.
⁶ School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China; Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, China. Electronic address: pengshuang@gzsport.edu.cn.
⁷ School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China; Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, China. Electronic address: liliangming@gzsport.edu.cn.

PMID: 38306800
DOI: 10.1016/j.bbadis.2024.167045

Abstract

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.

Keywords: Exercise; Lipid droplet; Lipophagy; Non-alcoholic fatty liver disease; PLIN2–LIPA axis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Disease Models, Animal
Lipid Droplets / metabolism
Lipid Metabolism Disorders* / metabolism
Mice
Non-alcoholic Fatty Liver Disease* / genetics
RNA, Messenger / metabolism

Substances

RNA, Messenger