Scavenger receptor CD36 mediates inhibition of cholesterol synthesisviaactivation of the PPARγ/PGC‐1α pathway and Insig1/2 expression in hepatocytes

Abstract

The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-1 and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insig1 and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor γ (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirt1-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-1α signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…Given that resistin was initially described as an adipokine increasing hepatic IR and glucose metabolism through an AMPK-dependent pathway, it is plausible that the activity of PGC-1α in the liver may be governed by a complex network of interactions among SIRT1, AMPK and PPARα. This is in accordance with another study that indicates a critical role of PGC-1α in cholesterol synthesis (Rodrigue-Way et al 2014). In addition, it is also reported that SIRT1/PGC-1α axis regulated glucose and lipid metabolism through a PPARα-independent pathway (Peeters et al 2011, Alberdi et al 2013.…”

Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome

“…Changes in acetyl-CoA, succinate, and C3DC (derived from malonyl-CoA) result from enhanced BCAA catabolism, fatty acid ȕ-oxidation, and lipogenesis in follicular cells of classic PCOS patients may aggravate the dysfunction of sirtuins and affect mitochondrial function of CCs. The decreased mitochondrial biogenesis in CCs may result from not only the methylation but also the deacetylation of PGC-1Į by SIRT1 [49]. The decrease ǻȌmand appearance of apoptotic bodies observed of CCs may be related with dysfunction SIRT3, which has a protective role in maintaining the ǻȌmand anti-apoptosis effect [50].…”

Mipu1 Inhibits Lipid Accumulation Through Down-Regulation of CD36 in RAW264.7 Cells

“…CD36 is the most important SR which uptakes oxLDL and contributes to the formation of foam cells [27,28]. To determine the functional significance of Mipu1 in foam-cell formation, we downregulated expression of endogenous Mipu1 in RAW264.7 cells.…”