Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice.

Autor: Luo HY; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Mu WJ; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Chen M; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Zhu JY; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Li Y; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Li S; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Yan LJ; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Li RY; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Yin MT; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Li X; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Chen HM; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., Guo L; School of Exercise and Health and Collaborative Innovation Center for Sports and Public Health, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai 200438, China; Key Laboratory of Exercise and Health Sciences of the Ministry of Education, Shanghai University of Sport, Shanghai 200438, China. Electronic address: guoliang@sus.edu.cn.
Jazyk: angličtina
Zdroj: Metabolism: clinical and experimental [Metabolism] 2024 Jun; Vol. 155, pp. 155916. Date of Electronic Publication: 2024 Apr 13.
DOI: 10.1016/j.metabol.2024.155916
Abstrakt: Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10 LKO ) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10 LTG ) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.
Competing Interests: Declaration of competing interest The authors declare no competing interests.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: