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Originally published In Press as doi:10.1194/jlr.M700345-JLR200 on August 28, 2007

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Journal of Lipid Research, Vol. 48, 2725-2735, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Fenofibrate reduces intestinal cholesterol absorption via PPAR{alpha}-dependent modulation of NPC1L1 expression in mouse

Mark A. Valasek*, Stephen L. Clarke* and Joyce J. Repa1,{dagger}

* Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390
{dagger} Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390

Published, JLR Papers in Press, August 28, 2007.

1 To whom correspondence should be addressed. e-mail: joyce.repa{at}utsouthwestern.edu

Fibrates, including fenofibrate, exert their biological effects by binding peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Treatment with PPAR{alpha} agonists enhances fatty acid oxidation, decreases plasma triglycerides, and may promote reverse cholesterol transport. In addition, fibrate administration can reduce intestinal cholesterol absorption in patients, although the molecular mechanism for this effect is unknown. Because Niemann-Pick C1-Like 1 (NPC1L1) is already known to be a critical protein for cholesterol absorption, we hypothesized that fenofibrate might modulate NPC1L1 expression to alter intestinal cholesterol transport. Here, we find that fenofibrate-treated wild-type mice have decreased fractional cholesterol absorption (35–47% decrease) and increased fecal neutral sterol excretion (51–83% increase), which correspond to decreased expression of NPC1L1 mRNA and protein (38–66% decrease) in the proximal small intestine. These effects of fenofibrate are dependent on PPAR{alpha}, as Ppar{alpha}-knockout mice fail to respond like wild-type littermates. Fenofibrate affects the ezetimibe-sensitive pathway and retains the ability to decrease cholesterol absorption and NPC1L1 mRNA expression in chow-fed liver X receptor {alpha}/ß-double-knockout mice and high-cholesterol- or cholic acid-fed wild-type mice. These data demonstrate that fenofibrate specifically acts via PPAR{alpha} to decrease cholesterol absorption at the level of intestinal NPC1L1 expression.

Supplementary key words dietary cholesterol • fractional cholesterol absorption • fecal dual-isotope method • real-time polymerase chain reaction • peroxisome proliferator-activated receptor {alpha} • Niemann-Pick C1-Like 1

Abbreviations: ACOX1, acyl-coenzyme A oxidase 1; CAV1, caveolin-1; CT, comparative cycle number at threshold; LXR, liver X receptor; mpk, milligrams per kilogram body weight; NPC1L1, Niemann-Pick C1-Like 1; PPAR{alpha}, peroxisome proliferator-activated receptor {alpha}; qRT, quantitative real-time; SR-BI, scavenger receptor class B type I


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