Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FASEB J. 2020 Apr;34(4):5658-5672. doi: 10.1096/fj.201902777RR. Epub 2020 Feb 25.
A contradictory role of CD36 in insulin resistance was found to be related to the nutrient state. Here, we examined that the physiological functions of CD36 in insulin signal transduction in mice fed a low-fat diet. CD36 deficiency led to hepatic insulin resistance and decreased insulin-stimulated tyrosine phosphorylation of insulin receptor β (IRβ) in mice fed a low-fat diet. The ability of insulin to bind with IR did not differ between WT and CD36-deficient hepatocytes. CD36 formed a complex with IRβ and dissociation of CD36/Fyn complex or inhibition of Fyn only partially reversed the effects of CD36 on hepatic insulin signaling. Furthermore, we found that CD36 deficiency led to abnormally increased hepatic protein-tyrosine phosphatase 1B (PTP1B) expression and enhanced PTP1B and IR interactions, which contributed to the decreased insulin signaling and disordered glucose metabolism. In addition, increased endoplasmic reticulum (ER) stress was found in the livers of the CD36-deficient mice, while inhibited ER stress normalized the PTP1B expression and restored insulin signaling in the CD36-deficient mice. Our findings suggest that the loss of CD36 impairs hepatic insulin signaling by enhancing the PTP1B/IR interaction that is induced by ER stress, indicating a possible critical step in the progression of hepatic insulin resistance.
CD36 在胰岛素抵抗中的矛盾作用与营养状态有关。在这里，我们研究了在低脂饮食喂养的小鼠中 CD36 在胰岛素信号转导中的生理功能。CD36 缺乏导致低脂饮食喂养的小鼠肝胰岛素抵抗和胰岛素刺激的胰岛素受体β（IRβ）酪氨酸磷酸化减少。WT 和 CD36 缺陷型肝细胞中胰岛素与 IR 的结合能力没有差异。CD36 与 IRβ 形成复合物，CD36/Fyn 复合物的解离或 Fyn 的抑制仅部分逆转了 CD36 对肝胰岛素信号的影响。此外，我们发现 CD36 缺乏导致肝蛋白酪氨酸磷酸酶 1B（PTP1B）表达异常增加，并增强了 PTP1B 和 IR 的相互作用，这导致胰岛素信号降低和葡萄糖代谢紊乱。此外，在 CD36 缺陷型小鼠的肝脏中发现内质网（ER）应激增加，而抑制 ER 应激可使 PTP1B 表达正常化并恢复 CD36 缺陷型小鼠的胰岛素信号。我们的研究结果表明，CD36 的缺失通过增强 ER 应激诱导的 PTP1B/IR 相互作用来损害肝胰岛素信号，这表明肝胰岛素抵抗进展中的一个关键步骤。
