Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to Fatty Acid Synthase
Yang Song,
Wei Zhong,
Harry Cheuk-Hay Lau,
Yating Zhang,
Huayu Guan,
Mingxu Xie,
Suki Ha,
Diwen Shou,
Yongjian Zhou,
Hongzhi Xu,
Jun Yu,
Xiang Zhang
Affiliations
Yang Song
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China; Department of Gastroenterology & Institute for Microbial Ecology & Xiamen Key Laboratory of Intestinal Microbiome and Human Health & Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China
Wei Zhong
Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
Harry Cheuk-Hay Lau
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China
Yating Zhang
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China
Huayu Guan
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China
Mingxu Xie
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China
Suki Ha
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China
Diwen Shou
Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou 510180, China
Yongjian Zhou
Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou 510180, China
Hongzhi Xu
Department of Gastroenterology & Institute for Microbial Ecology & Xiamen Key Laboratory of Intestinal Microbiome and Human Health & Clinical Research Center for Gut Microbiota and Digestive Diseases of Fujian Province, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361004, China; Corresponding authors.
Jun Yu
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China; Corresponding authors.
Xiang Zhang
Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; Shenzhen Research Institute, The Chinese Unviersity of Hong Kong, Shenzhen 518057, China; Corresponding authors.
Carboxyl ester lipase (CEL), a pivotal enzyme involved in lipid metabolism, is recurrently mutated in obese mice. Here, we aimed to elucidate the functional significance, molecular mechanism, and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific carboxyl ester lipase gene (Cel) knockout (CelΔHEP) and wildtype (WT) littermates were fed with choline-deficient high-fat diet (CD-HFD) for 16 weeks, or methionine- and choline-deficient diet (MCD) for three weeks to induce MASH. Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL. CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral, serotype 8 (AAV8) to induce specific overexpression of CEL in the liver. We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice. CelΔHEP mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis, inflammation, lipid peroxidation, and liver injury compared to WT littermates, accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. Consistently, Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation, whereas CEL overexpression exerted the opposite effect. Mechanistically, CEL directly bound to fatty acid synthase (FASN), resulting in reduced FASN SUMOylation, which in turn promoted FASN degradation through the proteasome pathway. Furthermore, inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro. Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD. CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis. CEL overexpression confers a therapeutic benefit in steatohepatitis.
