Role of the FOXM1/CMA/ER stress axis in regulating the progression of nonalcoholic steatohepatitis
Background and aim: The molecular mechanisms underlying the progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) remain unclear; however, the role of autophagy in these mechanisms has attracted extensive attention. This study aimed to investigate the role of chaperone-mediated autophagy (CMA) in NAFL-to-NASH progression and elucidate the underlying mechanisms. Methods: Hepatic CMA activity was analyzed in patients with NASH and mouse models of NASH. LAMP2A was knocked down or overexpressed to assess the effects of hepatocyte-specific CMA on NAFL-to-NASH progression. Mice were fed a high-fat diet or a methionine–choline-deficient diet to induce NAFL or NASH. Palmitic acid was used to mimic lipotoxicity-induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via chromatin immunoprecipitation and dual-luciferase reporter assay. Results: Hepatic CMA activity was substantially low in patients and mice with NASH. Knockdown of LAMP2A resulted in hepatocyte-specific CMA deficiency, which promoted hepatic inflammation and fibrosis in mice with NASH. In addition, CMA deficiency exacerbated endoplasmic reticulum (ER) stress and hepatocyte damage in vivo and in vitro. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of HMGCR, a rate-limiting enzyme of cholesterol synthesis, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. Restoration of hepatocyte-specific CMA activity effectively ameliorated diet-induced NASH and ER stress in vivo and in vitro. FOXM1 negatively regulated the transcription of LAMP2A by directly binding to its promoter. Upregulation of FOXM1 impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious circle and promoting the development of NASH. Conclusions: This study highlights the role of the FOXM1/CMA/ER stress axis in NAFL-to-NASH progression and proposes novel therapeutic targets for NASH. Overall design: To explore the transcriptional regulation of LAMP2A in NASH, transcriptomic analysis was performed in liver tissues from mice fed MCD for 4 weeks and those from mice fed a normal diet.