Hepatocyte CD36 protects mice from NASH diet-induced liver injury and fibrosis via blocking N1ICD production

作者全名："Li, Yuqi; Zhang, Linkun; Jiao, Junkui; Ding, Qiuying; Li, Yanping; Zhao, Zhibo; Luo, Jinfeng; Chen, Yaxi; Ruan, Xiongzhong; Zhao, Lei"

作者地址："[Li, Yuqi; Zhang, Linkun; Jiao, Junkui; Ding, Qiuying; Li, Yanping; Zhao, Zhibo; Luo, Jinfeng; Chen, Yaxi; Ruan, Xiongzhong; Zhao, Lei] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Ctr Lipid Res Key Lab Mol Biol Infect Dis,Minist E, Chongqing 400016, Peoples R China; [Ruan, Xiongzhong] UCL, Med Sch, Ctr Nephrol, John Moorhead Res Lab, London NW3 2PF, England"

通信作者："Zhao, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Ctr Lipid Res Key Lab Mol Biol Infect Dis,Minist E, Chongqing 400016, Peoples R China."

来源：BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001060434800001

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：1869

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：CD36; Notch1; & gamma;-Secretase; Fibrosis; Lipid rafts

摘要："Background & aims: Fatty acid translocase CD36 (CD36/FAT) is a widely expressed membrane protein with multiple immuno-metabolic functions. Genetic CD36 deficiency is associated with increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in patients. Liver fibrosis severity mainly affects the prognosis in patients with MAFLD, but the role of hepatocyte CD36 in liver fibrosis of MAFLD remains unclear.Methods: A high-fat high-cholesterol diet and a high-fat diet with high-fructose drinking water were used to induce nonalcoholic steatohepatitis (NASH) in hepatocyte-specific CD36 knockout (CD36LKO) and CD36flox/ flox (LWT) mice. Human hepG2 cell line was used to investigate the role of CD36 in regulating Notch pathway in vitro.Results: Compared to LWT mice, CD36LKO mice were susceptible to NASH diet-induced liver injury and fibrosis. The analysis of RNA-sequencing data revealed that Notch pathway was activated in CD36LKO mice. LY3039478, an inhibitor of ?-secretase, inhibited Notch1 protein S3 cleavage and Notch1 intracellular domain (N1ICD) production, alleviating liver injury and fibrosis in CD36LKO mice livers. Likewise, both LY3039478 and knockdown of Notch1 inhibited the CD36KO-induced increase of N1ICD production, causing the decrease of fibrogenic markers in CD36KO HepG2 cells. Mechanistically, CD36 formed a complex with Notch1 and ?-sec-retase in lipid rafts, and hence CD36 anchored Notch1 in lipid rafts domains and blocked Notch1/?-secretase interaction, inhibiting ?-secretase-mediated cleavage of Notch1 and the production of N1ICD.Conclusions: Hepatocyte CD36 plays a key role in protecting mice from diet-induced liver injury and fibrosis, which may provide a potential therapeutic strategy for preventing liver fibrogenesis in MAFLD."

基金机构："National Natural Science Foundation of China [81970510, 31971084, cstc2021ycjh-bgzxm0146]; Chongqing Natural Science Foundation [CQYC201905079]; Talent Project of Chongqing [W0062]; Science Fund for The Youth Innovation Team of Chongqing Medical University [CYB21175]; Postgraduate Research and Innovation Project of Chongqing Municipal Education Commission; [82270608]"

基金资助正文："Funding sources The work was supported by the National Natural Science Foundation of China (82270608, 81970510, 31971084) , Chongqing Natural Science Foundation (cstc2021ycjh-bgzxm0146) , Talent Project of Chongqing (CQYC201905079) , Science Fund for The Youth Innovation Team of Chongqing Medical University (W0062) , Postgraduate Research and Innovation Project of Chongqing Municipal Education Commission (CYB21175) ."