Fibrates Down-regulate Hepatic Scavenger Receptor Class B Type I Protein Expression in Mice

Abstract

Fibrates are normolipidemic drugs used in atherogenic dyslipidemia because of their ability to raise high density lipoprotein (HDL) and decrease triglyceride levels. They exert multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-␣ (PPAR-␣), which controls the transcriptional regulation of genes involved in hepatic fatty acid, cholesterol, and lipoprotein metabolism. The hepatic expression of the scavenger receptor class B type I (SR-BI) plays a critical role in lipoprotein metabolism, mainly due to its ability to mediate selective cholesterol uptake. Because fibrates and PPAR-␣ agonists upregulate SR-BI expression in human and murine macrophages, we tested whether fibrates raised a similar regulatory response on hepatic SR-BI expression in mice. Surprisingly, fibrate treatment suppressed SR-BI protein expression in the liver without changing steady state SR-BI mRNA levels. Decreased hepatic SR-BI protein expression correlated with enlarged HDL particle size. This effect was concomitant with down-regulation of CLAMP, a putative SR-BI-stabilizing protein found in the hepatic plasma membrane, which was also not associated to changes in CLAMP mRNA levels. The posttranscriptional regulatory effect of fibrates over hepatic SR-BI protein levels was dependent on PPAR-␣ expression, because it was absent in PPAR-␣-deficient mice. Restoring hepatic SR-BI expression in fibrate-treated mice by recombinant adenoviral gene transfer abolished fibrate-mediated HDL particle size enlargement. This study describes a novel effect of fibrates on hepatic SR-BI expression providing an alternative mechanism by which this drug family modulates HDL metabolism in vivo.

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

“…PPAR␣ agonists enhance SR-BI mRNA expression in macrophages but down-regulate SR-BI protein in hepatocytes. Fibrates have therefore been proposed to possibly regulate SR-BI protein synthesis, trafficking, degradation, and interaction with SR-BI adaptors, such as PDZK1 (36,37). Results presented here suggest that Mek1/2 inhibitors enhance PPAR␣-inducible proteasomal degradation pathways to down-regulate SR-BI in fibroblasts and hepatocytes, which is most relevant for the involvement of SR-BI in reverse cholesterol transport.…”

“…Results presented in this study suggest that Ras/MAPK signaling modulates SR-BI expression and activity via PPAR␣, a major regulator of cholesterol homeostasis (16,58). Yet the role of PPAR␣ in SR-BI expression is complex and can involve transcriptional and post-transcriptional mechanisms, depending on the cell type analyzed (2,29,36,37). PPAR␣ agonists enhance SR-BI mRNA expression in macrophages but down-regulate SR-BI protein in hepatocytes.…”

“…8C). Hence, the previously identified PPAR␣-inducible but PDZK1-independent SR-BI degradation in hepatocytes (36,37) appears to be stimulated by the inhibition of Mek1/2 kinases.…”

“…Because fibrates induce SR-BI degradation in liver (36, 37), we next analyzed SR-BI protein stability in human HuH7 hepatocytes. As shown for primary hepatocytes from fibrate-fed mice (36,37), Wy-14643 strongly down-regulated SR-BI protein levels in HuH7 cells (Fig. 7B, compare lanes 1 and 3).…”

“…Although the role of SR-BI for cholesterol efflux in peripheral cells is not fully understood (2,30,31), SR-BI is also highly expressed in liver to regulate hepatic uptake of HDL cholesteryl esters for excretion into bile (2,(32)(33)(34)(35). Surprisingly, in hepatocytes PPAR␣ activation induces SR-BI protein degradation and reduces SR-BI cell surface expression (36,37). The mechanisms that down-regulate hepatic SR-BI have yet to be fully elucidated.…”