Scavenger Receptor CD36 Mediates Inhibition of Cholesterol Synthesis via Activation of the LKB1-AMPK Pathway and Insig1/Insig2 Expression in Hepatocytes

Abstract

Scavenger receptor CD36 is known to play a central role in regulating lipid metabolism, in part, through the uptake of oxidized LDL in macrophages and its ability to internalize long chain fatty acids in adipocytes. Here, we demonstrate that CD36 activity impacts cholesterol synthesis in hepatocytes. Using hexarelin, a growth hormone-releasing peptide that interacts with CD36, we found a rapid phosphorylation of LKB1, which led to subsequent AMPK phosphorylation in treated HepG2 cells. HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis, was phosphorylated and inactivated following hexarelin treatment. This was accompanied with a significant degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway in response to CD36 activation and an enhanced recruitment of escort proteins Insig-1 and Insig-2. Key enzymes involved in cholesterol biosynthesis and under SREBP-2 control remained downregulated upon long-term hexarelin treatment despite sterol depletion. Increased expression of Insig-1 and Insig-2 in HepG2 cells was dependent on nuclear receptor PPARγ activation by hexarelin, providing a role for PPARγ in upregulating Insig expression. This study provides a mechanistic basis by which CD36 modulates HMG-CoA reductase function and Insig expression through activation of PPARγ, thereby supporting a novel role of scavenger receptor CD36 to regulate cholesterol synthesis in hepatocytes.