Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

Science. 2004 Feb 20;303(5661):1201-4. doi: 10.1126/science.1093131.

Abstract

Dietary cholesterol consumption and intestinal cholesterol absorption contribute to plasma cholesterol levels, a risk factor for coronary heart disease. The molecular mechanism of sterol uptake from the lumen of the small intestine is poorly defined. We show that Niemann-Pick C1 Like 1(NPC1L1) protein plays a critical role in the absorption of intestinal cholesterol. NPC1L1 expression is enriched in the small intestine and is in the brush border membrane of enterocytes. Although otherwise phenotypically normal, NPC1L1-deficient mice exhibit a substantial reduction in absorbed cholesterol, which is unaffected by dietary supplementation of bile acids. Ezetimibe, a drug that inhibits cholesterol absorption, had no effect in NPC1L1 knockout mice, suggesting that NPC1L1 resides in an ezetimibe-sensitive pathway responsible for intestinal cholesterol absorption.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anticholesteremic Agents / pharmacology
  • Azetidines / pharmacology
  • Cholesterol / metabolism*
  • Cholesterol, Dietary / metabolism*
  • Cholic Acid / administration & dosage
  • Cholic Acid / pharmacology
  • Computational Biology
  • Enterocytes / metabolism*
  • Ezetimibe
  • Female
  • Gene Expression Profiling
  • Humans
  • Intestinal Absorption* / drug effects
  • Intestine, Small / metabolism
  • Jejunum / metabolism
  • Liver / metabolism
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Anticholesteremic Agents
  • Azetidines
  • Cholesterol, Dietary
  • Membrane Proteins
  • Membrane Transport Proteins
  • NPC1L1 protein, human
  • NPC1L1 protein, rat
  • Npc1l1 protein, mouse
  • Proteins
  • Cholesterol
  • Ezetimibe
  • Cholic Acid