title: Mouse models of disturbed HDL metabolism.
abstract: High-density lipoprotein (HDL) is considered to be an anti-atherogenic lipoprotein moiety. Generation of genetically modified (total body and tissue-specific knockout) mouse models has significantly contributed to our understanding of HDL function. Here we will review data from knockout mouse studies on the importance of HDL's major alipoprotein apoA-I, the ABC transporters A1 and G1, lecithin:cholesterol acyltransferase, phospholipid transfer protein, and scavenger receptor BI for HDL's metabolism and its protection against atherosclerosis in mice. The initial generation and maturation of HDL particles as well as the selective delivery of its cholesterol to the liver are essential parameters in the life cycle of HDL. Detrimental atherosclerosis effects observed in response to HDL deficiency in mice cannot be solely attributed to the low HDL levels per se, as the low HDL levels are in most models paralleled by changes in non-HDL-cholesterol levels. However, the cholesterol efflux function of HDL is of critical importance to overcome foam cell formation and the development of atherosclerotic lesions in mice. Although HDL is predominantly studied for its atheroprotective action, the mouse data also suggest an essential role for HDL as cholesterol donor for steroidogenic tissues, including the adrenals and ovaries. Furthermore, it appears that a relevant interaction exists between HDL-mediated cellular cholesterol efflux and the susceptibility to inflammation, which (1) provides strong support for the novel concept that inflammation and metabolism are intertwining biological processes and (2) identifies the efflux function of HDL as putative therapeutic target also in other inflammatory diseases than atherosclerosis.
authors.affiliation: Division of Biopharmaceutics, Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands, hoekstra@lacdr.leidenuniv.nl.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000097:blood / Q000235:genetics; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D004195:Disease Models, Animal; D005838:Genotype; D008074:Lipoproteins / Q000097:blood / Q000235:genetics; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics; D049294:Phospholipid Transfer Proteins / Q000097:blood / Q000235:genetics; D065840:Protective Factors; D012307:Risk Factors; D051122:Scavenger Receptors, Class B / Q000097:blood / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D015415:Biomarkers; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008074:Lipoproteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D049294:Phospholipid Transfer Proteins; D051122:Scavenger Receptors, Class B; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C454739:Scarb1 protein, mouse; C510091:phospholipid transfer protein, mouse