title: A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine.
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.
authors: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors: Heleen M
authors: HM
authors: de Vogel-van den Bosch
authors: Nicole J W
authors: NJ
authors: de Wit
authors: Guido J E J
authors: GJ
authors: Hooiveld
authors: Hanneke
authors: H
authors: Vermeulen
authors: Jelske N
authors: JN
authors: van der Veen
authors: Sander M
authors: SM
authors: Houten
authors: Folkert
authors: F
authors: Kuipers
authors: Michael
authors: M
authors: Müller
authors: Roelof
authors: R
authors: van der Meer
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D006888:Hydroxycholesterols / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008074:Lipoproteins / Q000235:genetics; D000071518:Liver X Receptors; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000494:pharmacology
chemical_list: C577836:ABCA1 protein, human; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D006888:Hydroxycholesterols; D008074:Lipoproteins; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; C000605213:NR1H3 protein, human; C482445:Npc1l1 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; C076996:27-hydroxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases