Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse

Mark A. Valasek, Stephen L. Clarke, Joyce J. Repa

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Fibrates, including fenofibrate, exert their biological effects by binding peroxisome proliferator-activated receptor α (PPARα), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Treatment with PPARα 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 PPARα, as Pparα-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 α/β-double-knockout mice and high-cholesterol- or cholic acid-fed wild-type mice. These data demonstrate that fenofibrate specifically acts via PPARβ to decrease cholesterol absorption at the level of intestinal NPC1L1 expression.

Original languageEnglish (US)
Pages (from-to)2725-2735
Number of pages11
JournalJournal of Lipid Research
Volume48
Issue number12
DOIs
StatePublished - Dec 2007

Fingerprint

Fenofibrate
Peroxisome Proliferator-Activated Receptors
Intestinal Absorption
Cholesterol
Modulation
Fibric Acids
Knockout Mice
Cholic Acid
Messenger RNA
Sterols
Cytoplasmic and Nuclear Receptors
Liver
Small Intestine
Triglycerides
Proteins
Transcription Factors
Fatty Acids
Ligands
Plasmas
Oxidation

Keywords

  • Dietary cholesterol
  • Fecal dual-isotope method
  • Fractional cholesterol absorption
  • Niemann-Pick C1-like 1
  • Peroxisome proliferator-activated receptor α
  • Real-time polymerase chain reaction

ASJC Scopus subject areas

  • Endocrinology

Cite this

Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse. / Valasek, Mark A.; Clarke, Stephen L.; Repa, Joyce J.

In: Journal of Lipid Research, Vol. 48, No. 12, 12.2007, p. 2725-2735.

Research output: Contribution to journalArticle

@article{55e237b6b0444c71ab3dc27d70532e7b,
title = "Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse",
abstract = "Fibrates, including fenofibrate, exert their biological effects by binding peroxisome proliferator-activated receptor α (PPARα), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Treatment with PPARα 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 PPARα, as Pparα-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 α/β-double-knockout mice and high-cholesterol- or cholic acid-fed wild-type mice. These data demonstrate that fenofibrate specifically acts via PPARβ to decrease cholesterol absorption at the level of intestinal NPC1L1 expression.",
keywords = "Dietary cholesterol, Fecal dual-isotope method, Fractional cholesterol absorption, Niemann-Pick C1-like 1, Peroxisome proliferator-activated receptor α, Real-time polymerase chain reaction",
author = "Valasek, {Mark A.} and Clarke, {Stephen L.} and Repa, {Joyce J.}",
year = "2007",
month = "12",
doi = "10.1194/jlr.M700345-JLR200",
language = "English (US)",
volume = "48",
pages = "2725--2735",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "12",

}

TY - JOUR

T1 - Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse

AU - Valasek, Mark A.

AU - Clarke, Stephen L.

AU - Repa, Joyce J.

PY - 2007/12

Y1 - 2007/12

N2 - Fibrates, including fenofibrate, exert their biological effects by binding peroxisome proliferator-activated receptor α (PPARα), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Treatment with PPARα 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 PPARα, as Pparα-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 α/β-double-knockout mice and high-cholesterol- or cholic acid-fed wild-type mice. These data demonstrate that fenofibrate specifically acts via PPARβ to decrease cholesterol absorption at the level of intestinal NPC1L1 expression.

AB - Fibrates, including fenofibrate, exert their biological effects by binding peroxisome proliferator-activated receptor α (PPARα), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Treatment with PPARα 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 PPARα, as Pparα-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 α/β-double-knockout mice and high-cholesterol- or cholic acid-fed wild-type mice. These data demonstrate that fenofibrate specifically acts via PPARβ to decrease cholesterol absorption at the level of intestinal NPC1L1 expression.

KW - Dietary cholesterol

KW - Fecal dual-isotope method

KW - Fractional cholesterol absorption

KW - Niemann-Pick C1-like 1

KW - Peroxisome proliferator-activated receptor α

KW - Real-time polymerase chain reaction

UR - http://www.scopus.com/inward/record.url?scp=37249042184&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37249042184&partnerID=8YFLogxK

U2 - 10.1194/jlr.M700345-JLR200

DO - 10.1194/jlr.M700345-JLR200

M3 - Article

C2 - 17726195

AN - SCOPUS:37249042184

VL - 48

SP - 2725

EP - 2735

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 12

ER -