Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis  

作　　者：Qian Yu Chang Li Qinghui Niu Jigang Wang Zhaodi Che Ke Lei He Ren Boyi Ma Yixing Ren Pingping Luo Zhuming Fan Huan Zhang Zhaohui Liu George L.Tipoe Jia Xiao 

机构地区：[1]Tumor Immunology and Cytotherapy of Medical Research Center,and Center for GI Cancer Diagnosis and Treatment,the Affiliated Hospital of Qingdao University,Qingdao 266000,China [2]Bau Institute of Medical and Health Sciences Education and School of Biomedical Sciences,LKS Faculty of Medicine,the University of Hong Kong,Hong Kong 999077,China [3]School of Biomedical Sciences,the Chinese University of Hong Kong,Hong Kong 999077,China [4]Department of Liver Center,the Affiliated Hospital of Qingdao University,Qingdao 266000,China [5]Department of Pathology,the Affiliated Hospital of Qingdao University,Qingdao 266000,China [6]Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery,the First Affiliated Hospital of Jinan University,Guangzhou 510632,China [7]Department of General Surgery,and Institute of Hepato-Biliary-Pancreas and Intestinal Disease,Affiliated Hospital of North Sichuan Medical College,Nanchong 637000,China [8]Department of Applied Biology and Chemical Technology,the Hong Kong Polytechnic University,Hong Kong 999077,China [9]Research Center for Chinese Medicine Innovation,the Hong Kong Polytechnic University,Hong Kong 999077,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第6期2628-2644,共17页药学学报（英文版）

基　　金：partly supported by National Natural Science Foundation of China(82125026 and 82122009);Natural Science Foundation of Shandong Province(ZR2022QH241 and ZR2020ZD11,China);Seed Fund for Basic Research of University Research Committee of The University of Hong Kong(20161159263,Hong Kong,China)。

摘　　要：The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis(NASH)remain largely unknown.We aimed to elucidate the roles of hepatic cyclooxygenase 1(COX1)in autophagy and the pathogenesis of diet-induced steatohepatitis in mice.Human nonalcoholic fatty liver disease(NAFLD)liver samples were used to examine the protein expression of COX1 and the level of autophagy.Cox1^(Δhepa)mice and their wildtype littermates were generated and fed with 3 different NASH models.We found that hepatic COX1 expression was increased in patients with NASH and diet induced NASH mice models accompanied by impaired autophagy.COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy.Mechanistically,COX1 directly interacted with WD repeat domain,phosphoinositide interacting 2(WIPI2),which was crucial for autophagosome maturation.Adeno-associated virus(AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1^(Δhepa)mice,indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy.In conclusion,we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2.Targeting the COX1 WIPI2 axis may be a novel therapeutic strategy for NASH.

关 键 词：Autophagy Inflammation Lipid metabolism Nonalcoholic fatty liver disease Cyclooxygenase 1 Phosphatidylinositol 3-phosphate WD repeat domain Phosphoinositide interacting 2 Autophagosome maturation 

分 类 号：R575.5[医药卫生—消化系统] R-332[医药卫生—内科学]