Hepatocyte CD36 protects mice from NASH diet-induced liver injury and fibrosis via blocking N1ICD production.
Hepatocyte CD36 protects mice from NASH diet-induced liver injury and fibrosis via blocking N1ICD production.
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DOI：
10.1016/j.bbadis.2023.166800
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发表时间：
2023-07
期刊：
影响因子：
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通讯作者：
Yuqi Li;Linkun Zhang;Junkui Jiao;Qiuying Ding;Yanping Li;Zhibo Zhao;Jinfeng Luo;Yaxi Chen;Xiongzhong Ruan;Lei Zhao
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文献类型：
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作者：
Yuqi Li;Linkun Zhang;Junkui Jiao;Qiuying Ding;Yanping Li;Zhibo Zhao;Jinfeng Luo;Yaxi Chen;Xiongzhong Ruan;Lei Zhao
背景与目的脂肪酸转位酶CD 36（Fatty acid translocase CD 36/FAT）是一种广泛表达的具有多种免疫代谢功能的膜蛋白。遗传性CD 36缺乏与患者代谢功能障碍相关性脂肪肝（MAFLD）的风险增加相关。肝纤维化严重程度主要影响MAFLD患者的预后，但肝细胞CD 36在MAFLD肝纤维化中的作用尚不清楚。方法采用高脂高胆固醇饮食和高脂饮食加高果糖饮用水诱导肝细胞特异性CD 36基因敲除（CD 36 LKO）和CD 36 flox/flox（LWT）小鼠非酒精性脂肪性肝炎（NASH）。结果与LWT小鼠相比，CD 36 LKO小鼠更易发生NASH饮食诱导的肝损伤和肝纤维化。RNA测序结果显示，CD 36 LKO小鼠的Notch信号通路被激活。LY 3039478是一种γ-分泌酶抑制剂，可抑制Notch 1蛋白S3切割和Notch 1胞内结构域（N1 ICD）的产生，减轻CD 36 LKO小鼠肝脏的肝损伤和纤维化。同样地，LY 3039478和Notch 1的敲低都抑制了CD 36 KO诱导的N1 ICD产生的增加，导致CD 36 KO HepG 2细胞中纤维化标志物的减少。CD 36与Notch 1和γ-分泌酶在脂筏上形成复合物，从而将Notch 1锚定在脂筏结构域，阻断Notch 1/γ-分泌酶的相互作用，抑制γ-分泌酶介导的Notch 1切割和N1 ICD的产生。这可能为预防MAFLD的肝纤维化提供潜在的治疗策略。
Background & aimsFatty 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.MethodsA 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.ResultsCompared 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 γ-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 γ-secretase in lipid rafts, and hence CD36 anchored Notch1 in lipid rafts domains and blocked Notch1/γ-secretase interaction, inhibiting γ-secretase-mediated cleavage of Notch1 and the production of N1ICD.ConclusionsHepatocyte 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.