A Chemical Switch Regulates Fibrate Specificity for Peroxisome Proliferator-activated Receptor α (PPARα) VersusLiver X Receptor

Jeffrey Thomas,Kelli S Bramlett,Chahrzad Montrose,Patricia Foxworthy,Patrick I Eacho,Denis Mccann,Guoqing Cao,Anton Kiefer,Jeff Mccowan,Kuo-Long Yu,Timothy Grese,William W Chin,Thomas P Burris,Laura F Michael

doi:10.1074/jbc.m209629200

Abstract

Fenofibrate is clinically successful in treating hypertriglyceridemia and mixed hyperlipidemia presumably through peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent induction of genes that control fatty acid beta-oxidation. Lipid homeostasis and cholesterol metabolism also are regulated by the nuclear oxysterol receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta). Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs. Likewise, ester forms, but not carboxylic acid forms, of other members of the fibrate class of molecules antagonize the LXRs. The fibrate esters display greater affinity for LXRs than the corresponding fibric acids have for PPARalpha. Thus, these two nuclear receptors display a degree of conservation in their recognition of ligands; yet, the acid/ester moiety acts as a chemical switch that determines PPARalpha versus LXR specificity. Consistent with its LXR antagonistic activity, fenofibrate potently represses LXR agonist-induced transcription of hepatic lipogenic genes. Surprisingly, fenofibrate does not repress LXR-induced transcription of various ATP-binding cassette transporters either in liver or in macrophages, suggesting that fenofibrate manifests variable biocharacter in the context of differing gene promoters. These findings provide not only an unexpected mechanism by which fenofibrate inhibits lipogenesis but also the basis for examination of the pharmacology of an LXR ligand in humans.

Highlights

Developed as hypolipidemic therapeutic agents, the fibrate class of molecules has been extensively characterized as ligands for the nuclear receptor, peroxisome proliferator-activated receptor ␣ (PPAR␣)1 [1]
Fenofibrate Represses liver X receptor (LXR)-induced Expression of SREBP— To determine whether fenofibrate can repress de novo fatty acid synthesis at the level of gene transcription, we studied the regulation of sterol regulatory element-binding protein-1 (SREBP1)-mediated gene transcription by fenofibrate
We explored whether fenofibrate represses LXR-mediated induction of endogenous SREBP1 mRNA expression in HepG2 cells by quantitative PCR analysis (Fig. 1B)

Summary

Introduction

Developed as hypolipidemic therapeutic agents, the fibrate class of molecules has been extensively characterized as ligands for the nuclear receptor, peroxisome proliferator-activated receptor ␣ (PPAR␣)1 [1]. These findings provide an unexpected mechanism by which fenofibrate ester inhibits SREBP1 transcription and lipogenesis without negating the beneficial role LXR that plays in mediating secretion of sterols from the liver and in increasing reverse cholesterol transport from macrophages.

Results

Conclusion