title: Genetic variant of the scavenger receptor BI in humans.
abstract: BACKGROUND
  In mice, the scavenger receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice. It is unclear what role SR-BI plays in human metabolism.
  
  
  METHODS
  We sequenced the gene encoding SR-BI in persons with elevated HDL cholesterol levels and identified a family with a new missense mutation (P297S). The functional effects of the P297S mutation on HDL binding, cellular cholesterol uptake and efflux, atherosclerosis, platelet function, and adrenal function were studied.
  
  
  RESULTS
  Cholesterol uptake from HDL by primary murine hepatocytes that expressed mutant SR-BI was reduced to half of that of hepatocytes expressing wild-type SR-BI. Carriers of the P297S mutation had increased HDL cholesterol levels (70.4 mg per deciliter [1.8 mmol per liter], vs. 53.4 mg per deciliter [1.4 mmol per liter] in noncarriers; P<0.001) and a reduced capacity for efflux of cholesterol from macrophages, but the carotid artery intima-media thickness was similar in carriers and in family noncarriers. Platelets from carriers had increased unesterified cholesterol content and impaired function. In carriers, adrenal steroidogenesis was attenuated, as evidenced by decreased urinary excretion of sterol metabolites, a decreased response to corticotropin stimulation, and symptoms of diminished adrenal function.
  
  
  CONCLUSIONS
  We identified a family with a functional mutation in SR-BI. The mutation carriers had increased HDL cholesterol levels and a reduction in cholesterol efflux from macrophages but no significant increase in atherosclerosis. Reduced SR-BI function was associated with altered platelet function and decreased adrenal steroidogenesis. (Funded by the European Community and others.).
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Vergeer
authors.forename: Suzanne J A
authors.initials: SJ
authors.lastname: Korporaal
authors.forename: Remco
authors.initials: R
authors.lastname: Franssen
authors.forename: Illiana
authors.initials: I
authors.lastname: Meurs
authors.forename: Ruud
authors.initials: R
authors.lastname: Out
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Sierts
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Mohammad Mahdi
authors.initials: MM
authors.lastname: Motazacker
authors.forename: Adriaan G
authors.initials: AG
authors.lastname: Holleboom
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
mesh_terms: D000293:Adolescent; D000311:Adrenal Glands / Q000502:physiology; D000309:Adrenal Insufficiency / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics*; D002339:Carotid Arteries / Q000033:anatomy & histology; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood*; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D015539:Platelet Activation / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics*; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D008076:Cholesterol, HDL; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D002784:Cholesterol; D006854:Hydrocortisone