title: Human ATP-binding cassette G1 controls macrophage lipoprotein lipase bioavailability and promotes foam cell formation.
abstract: OBJECTIVE
  The physiological function of the ATP-binding cassette G1 (ABCG1) transporter in humans is not yet elucidated, as no genetic disease caused by ABCG1 mutations has been documented. The goal of our study was, therefore, to investigate the potential role(s) of ABCG1 in lipid metabolism in humans.
  
  
  RESULTS
  Here we report that among the 104 polymorphisms present in the ABCG1 gene, the analysis of the frequent functional rs1893590 and rs1378577 single nucleotide polymorphisms located in the regulatory region of ABCG1 in the Regression Growth Evaluation Statin Study population revealed that both ABCG1 single nucleotide polymorphisms were significantly associated with plasma lipoprotein lipase (LPL) activity. Moreover, we observed that plasma LPL activity was modestly reduced in Abcg1(-/-) mice as compared with control mice. Adipose tissue and skeletal muscle are the major tissues accounting for levels and activity of plasma LPL in the body. However, beyond its lipolytic action in the plasma compartment, LPL was also described to act locally at the cellular level. Thus, macrophage LPL was reported to promote foam cell formation and atherosclerosis in vivo. Analysis of the relationship between ABCG1 and LPL in macrophages revealed that the knockdown of ABCG1 expression (ABCG1 knockdown) in primary cultures of human monocyte-derived macrophages using small interfering RNAs led to a marked reduction of both the secretion and activity of LPL. Indeed, LPL was trapped at the cell surface of ABCG1 knockdown human monocyte-derived macrophages, likely in cholesterol-rich domains, thereby reducing the bioavailability and activity of LPL. As a consequence, LPL-mediated lipid accumulation in human macrophage foam cells in the presence of triglyceride-rich lipoproteins was abolished when ABCG1 expression was repressed.
  
  
  CONCLUSIONS
  We presently report that ABCG1 controls LPL activity and promotes lipid accumulation in human macrophages in the presence of triglyceride-rich lipoproteins, thereby suggesting a potential deleterious role of macrophage ABCG1 in metabolic situations associated with high levels of circulating triglyceride-rich lipoproteins together with the presence of macrophages in the arterial wall.
authors: INSERM, UMR_S939, Paris, F-75013, France.
authors: Maryline
authors: M
authors: Olivier
authors: Michael W
authors: MW
authors: Tanck
authors: Ruud
authors: R
authors: Out
authors: Elise F
authors: EF
authors: Villard
authors: Bart
authors: B
authors: Lammers
authors: Laura
authors: L
authors: Bouchareychas
authors: Eric
authors: E
authors: Frisdal
authors: Alexandre
authors: A
authors: Superville
authors: Theo
authors: T
authors: Van Berkel
authors: John J
authors: JJ
authors: Kastelein
authors: Miranda Van
authors: MV
authors: Eck
authors: J Wouter
authors: JW
authors: Jukema
authors: M John
authors: MJ
authors: Chapman
authors: Geesje M
authors: GM
authors: Dallinga-Thie
authors: Maryse
authors: M
authors: Guerin
authors: Wilfried
authors: W
authors: Le Goff
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D016009:Chi-Square Distribution; D002784:Cholesterol / Q000378:metabolism; D005487:Foam Cells / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008071:Lipoprotein Lipase / Q000097:blood*; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; C548261:LPL protein, human; D008071:Lipoprotein Lipase