title: Lipid absorption defects in intestine-specific microsomal triglyceride transfer protein and ATP-binding cassette transporter A1-deficient mice.
abstract: We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92-95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations.
authors.affiliation: From the Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203 and.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: the Department of Pathology, Section on Lipid Sciences and Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 25157.
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: From the Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203 and. Electronic address: Mahmood.Hussain@downstate.edu.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids / Q000097:blood*; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002334:Carnitine O-Palmitoyltransferase; D002352:Carrier Proteins; D008055:Lipids; D047495:PPAR gamma; C577833:Abca1 protein, mouse; C106092:microsomal triglyceride transfer protein
keywords: ABCA1; Cholesterol; Intestine; Lipid Absorption; Lipid Metabolism; Lipids; Lipoprotein Secretion; Lipoprotein Structure; MTP; Triglyceride
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