CD36
脂肪生成
甾醇调节元件结合蛋白
脂肪变性
肝细胞
化学
脂肪酸合酶
非酒精性脂肪肝
胰岛素抵抗
脂毒性
生物
内分泌学
内科学
脂质代谢
细胞生物学
脂肪肝
生物化学
胰岛素
医学
胆固醇
甾醇
体外
基因
疾病
作者
Han Zeng,Hong Qin,Meng Liao,Enze Zheng,Xiaofang Luo,Anhua Xiao,Yiyu Li,Lin Chen,Li Wei,Lei Zhao,Xiong Z. Ruan,Ping Yang,Yaxi Chen
标识
DOI:10.1016/j.molmet.2021.101428
摘要
Enhanced de novo lipogenesis (DNL) in hepatocytes is a major contributor to nonalcoholic fatty liver disease (NAFLD). Fatty acid translocase (FAT/CD36) is involved in the pathogenesis of NAFLD through facilitating free fatty acids uptake. Here, we explored the effects of CD36 on DNL and elucidated the underlying mechanisms.We generated hepatocyte-specific CD36 knockout (CD36LKO) mice to study in vivo effects of CD36 on DNL under high-fat diet (HFD). Lipid deposition and DNL were analyzed in primary hepatocytes isolated from CD36LKO mice or HepG2 cells with CD36 overexpression. RNA sequence, co-immunoprecipitation, and proximity ligation assay were carried out to determine its role in regulating DNL.Hepatic CD36 expression was upregulated in NAFLD mice and patients, and CD36LKO mice exhibited attenuated HFD-induced hepatic steatosis and insulin resistance. We identified hepatocyte CD36 as a key regulator for DNL in the liver. Sterol regulatory element-binding protein 1 (SREBP1) and its downstream lipogenic enzymes such as FASN, ACCα, and ACLY were significantly downregulated in the liver of HFD-fed CD36LKO mice, whereas overexpression CD36 stimulated insulin-mediated DNL and lipid droplet formation in vitro. Mechanistically, CD36 was activated by insulin and formed a complex with insulin-induced gene-2 (INSIG2) that disrupts the interaction between SREBP cleavage-activating protein (SCAP) and INSIG2, thereby leading to the translocation of SREBP1 from ER to Golgi for processing. Furthermore, treatment with 25-hydroxycholesterol or betulin molecules shown to enhance SCAP-INSIG interaction, reversed the effects of CD36 on SREBP1 cleavage.Our findings identify a previously unsuspected role of CD36 in the regulation of hepatic lipogenic program through mediating SREBP1 processing by INSIG2, providing additional evidence for targeting CD36 in NAFLD.
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