A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine

Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1171-80. doi: 10.1152/ajpgi.00360.2007. Epub 2008 Mar 20.

Abstract

Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1, Abcg5, and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1, Abca1, Abcg5, and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% (P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRalpha-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRalpha independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat.

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Bile Acids and Salts / analysis
  • Cholesterol / blood
  • Cholesterol / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Dietary Fats / administration & dosage
  • Dietary Fats / pharmacology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Feces / chemistry
  • Gene Expression Regulation / drug effects
  • Hydroxycholesterols / pharmacology
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Intestinal Absorption / drug effects
  • Intestinal Absorption / physiology
  • Intestine, Small / cytology
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism*
  • Lipoproteins / genetics
  • Liver X Receptors
  • Male
  • Membrane Transport Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Oligonucleotide Array Sequence Analysis
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triglycerides / pharmacology

Substances

  • ABCA1 protein, human
  • ABCG5 protein, mouse
  • ABCG8 protein, mouse
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters
  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Dietary Fats
  • Hydroxycholesterols
  • Lipoproteins
  • Liver X Receptors
  • Membrane Transport Proteins
  • NR1H3 protein, human
  • Npc1l1 protein, mouse
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Triglycerides
  • 27-hydroxycholesterol
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases