HDAC6 inhibitor ACY-1215 protects from nonalcoholic fatty liver disease via inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway
Shifeng Fu,
Mengmeng Xu,
Jianglei Li,
Meihong Yu,
Siyi Wang,
Liu Han,
Rong Li,
Feihong Deng,
Hailing Peng,
Deliang Liu,
Yuyong Tan
Affiliations
Shifeng Fu
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Mengmeng Xu
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Jianglei Li
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Meihong Yu
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Siyi Wang
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Liu Han
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Rong Li
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Feihong Deng
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China
Hailing Peng
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China; Longshan County People's Hospital, Longshan, 416899, Hunan Province, China
Deliang Liu
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China; Corresponding author. No.139 Renmin Road, Furong district, Changsha city, Hunan province, China.
Yuyong Tan
Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China; Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan Province, China; Clinical Research Center of Digestive Diseases of Hunan Province, Changsha, 410011, Hunan Province, China; Corresponding author. No.139 Renmin Road, Furong district, Changsha city, Hunan province, China.
Background & aims: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic steatosis, for which there is currently no effective treatment. ACY-1215 is a selective inhibitor of histone deacetylation 6, which has shown therapeutic potential in many tumors, as well as acute liver injury. However, no research about ACY-1215 on NAFLD has been published. Therefore, our study aims to explore the role and mechanism of ACY-1215 in the experimental model of NAFLD, to propose a new treatment strategy for NAFLD. Methods: We established cell and animal models of NAFLD and verified the effect of ACY-1215 on NAFLD. The mechanism of ACY-1215 on NAFLD was preliminarily explored through TMT relative quantitative proteomics, and then we verify the mechanism discovered in the experimental model of NAFLD. Results: ACY-1215 can reduce lipid aggregation, IL-1β, and TNF α mRNA levels in liver cells in vitro. ACY-1215 can reduce the weight gain and steatosis in the liver of the NAFLD mouse model, alleviate the deterioration of liver function, and reduce IL-1βs and TNF α mRNA levels in hepatocytes. TMT relative quantitative proteomics found that ACY-1215 decreased the expression of CD14 in hepatocytes. It was found that ACY-1215 can inhibit the activation level of CD14/TLR4/MyD88/MAPK/NFκB pathway in the NAFLD experimental model. Conclusions: ACY-1215 has a protective effect on the cellular model of NAFLD induced by fatty acids and lipopolysaccharide, as well as the C57BL/6J mouse model induced by a high-fat diet. ACY-1215 may play a protective role by inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.
