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
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Amino Acid Sequence
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Animals
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Anticholesteremic Agents / pharmacology
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Azetidines / pharmacology
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Cholesterol / metabolism*
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Cholesterol, Dietary / metabolism*
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Cholic Acid / administration & dosage
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Cholic Acid / pharmacology
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Computational Biology
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Enterocytes / metabolism*
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Ezetimibe
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Female
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Gene Expression Profiling
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Humans
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Intestinal Absorption* / drug effects
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Intestine, Small / metabolism
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Jejunum / metabolism
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Liver / metabolism
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Male
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Membrane Transport Proteins / chemistry
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Sequence Data
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Oligonucleotide Array Sequence Analysis
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Proteins / chemistry
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Proteins / genetics
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Proteins / metabolism*
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Rats
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Rats, Sprague-Dawley
Substances
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Anticholesteremic Agents
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Azetidines
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Cholesterol, Dietary
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Membrane Proteins
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Membrane Transport Proteins
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NPC1L1 protein, human
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NPC1L1 protein, rat
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Npc1l1 protein, mouse
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Proteins
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Cholesterol
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Ezetimibe
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Cholic Acid