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

Mark A Valasek1, Stephen L Clarke, Joyce J Repa

  • 1Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Journal of Lipid Research
|August 30, 2007
PubMed

Insights

Fenofibrate, a PPARalpha agonist, reduces cholesterol absorption by decreasing intestinal NPC1L1 expression. This mechanism is PPARalpha-dependent and impacts cholesterol transport.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Fibrates, like fenofibrate, activate peroxisome proliferator-activated receptor alpha (PPARalpha).
  • PPARalpha agonists influence lipid metabolism, including fatty acid oxidation and triglyceride levels.
  • Fibrates are known to reduce intestinal cholesterol absorption, but the underlying mechanism is unclear.

Purpose of the Study:

  • To investigate the molecular mechanism by which fenofibrate reduces intestinal cholesterol absorption.
  • To determine if fenofibrate modulates the expression of Niemann-Pick C1-Like 1 (NPC1L1), a key protein in cholesterol absorption.

Main Methods:

  • Fenofibrate treatment in wild-type and PPARalpha-knockout mice.
  • Measurement of fractional cholesterol absorption and fecal sterol excretion.
  • Quantification of NPC1L1 mRNA and protein expression in the small intestine.
  • Experiments in liver X receptor alpha/beta-double-knockout mice and under various dietary conditions.

Main Results:

  • Fenofibrate treatment significantly decreased fractional cholesterol absorption and increased fecal sterol excretion in wild-type mice.
  • These effects correlated with a significant decrease in NPC1L1 mRNA and protein expression in the proximal small intestine.
  • PPARalpha-knockout mice did not exhibit these changes, indicating a PPARalpha-dependent mechanism.
  • Fenofibrate's effects on cholesterol absorption and NPC1L1 expression were observed independently of liver X receptor status and dietary challenges.

Conclusions:

  • Fenofibrate specifically decreases intestinal cholesterol absorption through a PPARalpha-dependent mechanism.
  • The drug modulates cholesterol transport by downregulating the expression of NPC1L1 in the small intestine.

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