Loss of CD36 impairs hepatic insulin signaling by enhancing the interaction of PTP1B with IR.

Yang P, Zeng H, Tan W, Luo X, Zheng E, Zhao L, Wei L, Ruan XZ, Chen Y, Chen Y,

FASEB J. 2020 Apr;34(4)

Abstract

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.