Srbl maps to mouse Chromosome 5 in a region harboring putative QTLs for plasma lipoprotein levels

Welch, Carrie L.; Xia, Yu‐Rong; Gu, Lin; Machleder, Dietrich; Mehrabian, Margarete; Wen, Ping-Zi; Webb, Nancy R.; Villiers, Willem J.S. de; Westhuyzen, Deneys van der; Lusis, A. J.

doi:10.1007/s003359900643

Cited by 15 publications

(8 citation statements)

References 9 publications

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“…Moreover, the SR-BI gene has been assigned to mouse chromosome 5, in a region homologous with human chromosome 12 harboring the SR-BI locus. Several of the previously indicated candidate genes related to lipids have been found in the mouse homologous region (MVK, ACADS, and TCF1), 24 and more careful analysis of these loci appears to be warranted.…”

Section: Table 7 Anthropometric Characteristics and Plasma Lipid Conmentioning

confidence: 99%

Association of Polymorphisms at the SR-BI Gene Locus With Plasma Lipid Levels and Body Mass Index in a White Population

Acton

Osgood

Donoghue

et al. 1999

ATVB

193

158

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Abstract-The scavenger receptor class B type I (SR-BI) is a lipoprotein receptor that has been shown to be important in high density lipoprotein cholesterol (HDL-C) metabolism in mice. To determine its role in humans, we have characterized the human SR-BI gene and investigated its genetic variation in 489 white men and women. Five variants were demonstrated: 2 in introns (3 and 5) and 3 in exons (1, 8, and 11). Three variants at exons 1 and 8 and intron 5 with allele frequencies Ͼ0.1 were used to examine associations with lipid or anthropometric variables. The exon 1 variant was significantly (PϽ0.05) associated with increased HDL-C and lower low density lipoprotein cholesterol (LDL-C) values in men, but no associations were observed in women. The exon 8 variant was associated in women with lower LDL-C concentrations (3.05Ϯ0.98 mmol/L and 3.00Ϯ0.93 mmol/L for heterozygotes and homozygotes, respectively) compared with women homozygous for the common allele T he scavenger receptor class B type I (SR-BI) is a multilipoprotein receptor found in the liver and steroidogenic glands of both mice 1 and humans 2,3 (for a review, see Reference 4). The cDNA for human SR-BI (also known as CLA-1) was originally cloned by homology to human CD36 and rat LIMPII, which are members of a family of transmembrane proteins. 5 An independent expression cloning study identified the hamster homologue by its ability to mediate the binding of modified LDL, and it was also shown to bind native LDL. 6 Subsequently, murine SR-BI was shown to mediate the uptake of lipid, but not apoprotein, from HDL into cells, 1 a process described as selective uptake. [7][8][9] This finding established SR-BI as the first HDL transmembrane receptor to be identified and cloned. Further studies of the human homologue demonstrated that it also is a multilipoprotein receptor that binds HDL, LDL, and VLDL. 2,10 Further analysis in vivo in mice and rats has supported a role for SR-BI in cholesterol metabolism. Targeted disruption of apoAI, the major protein component of HDL, leads to an increase in SR-BI expression in the adrenal glands of mice, 11 where HDL-C is used for steroid hormone synthesis. In addition, SR-BI expression levels in the adrenal glands are increased in response to adrenocorticotropic hormone and decreased in response to dexamethasone. 12 Estrogen treatment at high doses in rats greatly reduces SR-BI expression in the liver while it increases SR-BI expression in the adrenal gland and ovarian corpus luteal cells. 13 Transient overexpression of SR-BI in the livers of mice by adenoviral infection leads to a marked reduction in plasma HDL levels and a concomitant increase in plasma LDL/IDL cholesterol levels. 14 Finally, targeted disruption of the SR-BI gene in mice leads to a significant increase in plasma HDL 15,16 and reduced selective uptake of cholesterol from HDL into the liver. 16 Thus, SR-BI has clearly been shown to be a very important player in HDL metabolism in mice. However, although mice have HDL as the major cholesterol-carrying lipopr...

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Section: Table 7 Anthropometric Characteristics and Plasma Lipid Conmentioning

confidence: 99%

Association of Polymorphisms at the SR-BI Gene Locus With Plasma Lipid Levels and Body Mass Index in a White Population

Acton

Osgood

Donoghue

et al. 1999

ATVB

193

158

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“…36 Recently, we mapped this gene to mouse Chr 5, adjacent to the microsatellite marker D5Mit10. 37 The SRB-1 protein has been shown to bind various lipoproteins, including HDL, with high affinity. It is expressed primarily in liver and nonplacental steroidogenic tissues and mediates selective cholesterol uptake by a mechanism distinct from the classic LDL receptor pathway.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Trait Locus Analysis of Plasma Lipoprotein Levels in an Autoimmune Mouse Model

Johnson

Lusis

1999

ATVB

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Abstract-The autoimmune MRL/lpr mouse strain, a model for systemic lupus erythematosus, exhibited an unusual plasma lipoprotein profile, suggesting a possible interaction of autoimmune disease and lipoprotein metabolism.In an effort to examine the genetic basis of such interactions, and to study their relationship to atherogenesis, we performed a quantitative trait locus analysis using a total of 272 (MRL/lprϫBALB/cJ) second generation (F2) intercross mice. These mice were examined for levels of total plasma cholesterol, HDL cholesterol, VLDL and LDL cholesterol, unesterified cholesterol, autoantibodies, and aortic fatty streak lesions. Key Words: linkage analysis Ⅲ antibodies, antinuclear Ⅲ genes Ⅲ lupus erythematosus, systemic Ⅲ HDL P lasma lipoprotein levels are an important determinant of atherosclerosis, the major cause of coronary artery disease (CAD) and stroke. High levels of LDL and VLDL are strongly associated with increased incidence of CAD, whereas HDL has a protective effect. 1-4 Although a number of mendelian disorders contributing to lipoprotein metabolism, such as those of the LDL receptor in familial hypercholesterolemia and cholesterol ester transfer protein deficiency in hyperalphalipoproteinemia, have been elucidated, 1,5,6 they explain only a small fraction of the population variance of plasma lipoprotein levels. As yet, relatively little is known of the genetic factors contributing to common, complex genetic variations. Studies of such variations in humans are complicated by dietary influences and genetic heterogeneity. Animal models have significant advantages for the analysis of complex traits 7-11 ; in particular, planned breeding can be performed and the environment can be controlled. The mouse, the most useful mammal for genetic studies, has been developed as a model for the analysis of lipoprotein metabolism and other traits relevant to atherosclerosis. In previous studies in our laboratory, we have identified several quantitative-trait loci (QTL) for lipoprotein metabolism in mice, and some of the underlying genes were elucidated using a positional candidate gene strategy. 10,11

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“…In einem weiteren QTL auf Chromosom 5 [70] befinden sich die Gene des Cholecystokinin-Rezeptors (Cckar) und des HDL-Rezeptors (Srb1) als Gallenstein-Kandidatengene [71,72]. Die funktionelle Rolle des SRB1-Rezeptors wird daran deutlich, dass seine adenovirusvermittelte Überexpression in Hepatozyten bei Mäusen zu erniedrigten HDL-Cholesterinspiegeln im Serum sowie zu einer erhöhten Sekretion von biliärem Cholesterin führt [73,74] und dass auch die C57L-Gallensteinmaus Srb1 -wie oben erwähnt -überexprimiert und verminderte HDL-Spiegel aufweist [53].…”

Section: üBersichtenunclassified

Molekulargenetik der Cholesterin-Cholelithiasis: Identifizierung humaner und muriner Gallensteingene

Figge

Matern²,

Lammert³

2002

Z Gastroenterol

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Cholesterol cholelithiasis is one of the most common gastroenterological diseases in Western countries. It is a polygenic disease resulting from disturbed biliary cholesterol homeostasis. Association studies identified six human gallstone candidate genes. Polymorphisms in the genes encoding the apolipoproteins B and E, phospholipid flippase ( ABCB4), cholesterol ester transfer protein ( CETP), cholesterol-7alpha-hydroxylase ( CYP7A1) and ileal bile acid transporter ( SLC10A2) are correlated with gallstone prevalence. Quantitative Trait Locus (QTL) analysis localises additional unknown gallstone genes in inbred mice. Based on the natural variation of cholesterol gallstone susceptibility among different inbred strains, 5 lithogenic ( Lith) loci have been identified. Hepatobiliary transporters (e. g. bile salt export pump Abcb11) and key proteins of the lipoprotein metabolism (e. g. hepatic lipase Lipc) could be established as creedal candidate genes for Lith loci. The rapid progress of mouse and human genome projects provides the basis for the analysis of orthologous human LITH genes in gallstone patients, which might offer new prospects for individual risk assessment and molecular targets for stone prevention.

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Srbl maps to mouse Chromosome 5 in a region harboring putative QTLs for plasma lipoprotein levels

Cited by 15 publications

References 9 publications

Association of Polymorphisms at the SR-BI Gene Locus With Plasma Lipid Levels and Body Mass Index in a White Population

Association of Polymorphisms at the SR-BI Gene Locus With Plasma Lipid Levels and Body Mass Index in a White Population

Quantitative Trait Locus Analysis of Plasma Lipoprotein Levels in an Autoimmune Mouse Model

Molekulargenetik der Cholesterin-Cholelithiasis: Identifizierung humaner und muriner Gallensteingene

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