title: Intestinal SR-BI is upregulated in insulin-resistant states and is associated with overproduction of intestinal apoB48-containing lipoproteins.
abstract: Intestinal lipid dysregulation is a common feature of insulin-resistant states. The present study investigated alterations in gene expression of key proteins involved in the active absorption of dietary fat and cholesterol in response to development of insulin resistance. Studies were conducted in two diet-induced animal models of insulin resistance: fructose-fed hamster and high-fat-fed mouse. Changes in the mRNA abundance of lipid transporters, adenosine triphosphate cassette (ABC) G5, ABCG8, FA-CoA ligase fatty acid translocase P4, Niemann-Pick C1-Like1 (NPC1L1), fatty acid transport protein 4 (FATP4), and Scavenger Receptor Class B Type I (SR-BI), were assessed in intestinal fragments (duodenum, jejunum, and ileum) using quantitative real-time PCR. Of all the transporters evaluated, SR-B1 showed the most significant changes in both animal models examined. A marked stimulation of SR-B1 expression was observed in all intestinal segments examined in both insulin-resistant animal models. The link between SR-BI expression and intestinal lipoprotein production was then examined in the Caco-2 cell model. SR-B1 overexpression in Caco-2 cells increased apolipoprotein B (apoB) 100 and apoB48 secretion, whereas RNAi knock down of SR-B1 decreased secretion of both apoB100 and apoB48. We also observed changes in subcellular distribution of SR-B1 in response to exogenous lipid and insulin. Confocal microscopy revealed marked changes in SR-BI subcellular distribution in response to both exogenous lipids (oleate) and insulin. In summary, marked stimulation of intestinal SR-BI occurs in vivo in animal models of diet-induced insulin resistance, and modulation of SR-BI in vitro regulates production of apoB-containing lipoprotein particles. We postulate that apical and/or basolateral SR-BI may play an important role in intestinal chylomicron production and may contribute to chylomicron overproduction normally observed in insulin-resistant states.
authors.affiliation: Molecular Structure & Function, Research Institute, The Hospital for Sick Children, University of Toronto, Canada.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Hayashi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Webb
authors.forename: Joanna
authors.initials: J
authors.lastname: Choi
authors.forename: Chris
authors.initials: C
authors.lastname: Baker
authors.forename: Marsel
authors.initials: M
authors.lastname: Lino
authors.forename: Bernardo
authors.initials: B
authors.lastname: Trigatti
authors.forename: Karin E
authors.initials: KE
authors.lastname: Trajcevski
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hawke
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: 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 / Q000378:metabolism; D000818:Animals; D053283:Apolipoprotein B-48 / Q000096:biosynthesis*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006224:Cricetinae; D004041:Dietary Fats / Q000494:pharmacology*; D004386:Duodenum / Q000378:metabolism; D050171:Dyslipidemias; D005215:Fasting / Q000502:physiology; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology*; D015870:Gene Expression; D007082:Ileum / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D019518:Postprandial Period / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D053283:Apolipoprotein B-48; D018955:CD36 Antigens; D004041:Dietary Fats; D050612:Fatty Acid Transport Proteins; D007328:Insulin; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D012333:RNA, Messenger; C493572:Slc27a4 protein, mouse; D005632:Fructose