CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing

Mol Metab. 2022 Mar:57:101428. doi: 10.1016/j.molmet.2021.101428. Epub 2021 Dec 30.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CD36; INSIG2; Lipogenesis; NAFLD; SREBP1 processing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / metabolism*
  • Hepatocytes / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipogenesis* / physiology
  • Membrane Proteins* / metabolism
  • Mice
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*

Substances

  • CD36 Antigens
  • Cd36 protein, mouse
  • Insig2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1