Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice

Paigen, Beverly; Schork, Nicholas J.; Svenson, Karen L.; Cheah, Yin-Chai; Mu, Jian-Long; Lammert, Frank; Wang, David Q.–H.; Bouchard, Guylaine; Carey, Martin C.

doi:10.1152/physiolgenomics.2000.4.1.59

Cited by 73 publications

(62 citation statements)

References 35 publications

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“…The gallstone presence scan (Fig. 4A) detected a significant QTL (D2Mit94, peak 52 cM) that confirmed the previously detected QTL, Lith1 (11,16), and a suggestive QTL on chr 6 (D6Mit86, peak 0 cM); the latter locus became significant diet. An acute biliary fistula was fashioned and hepatic bile collected via the gallbladder for 60 min.…”

Section: Qtl Analysessupporting

confidence: 83%

“…Our ultimate goal is to identify genes that carry polymorphisms determining cholesterol gallstone susceptibility (i.e., Lith genes) (13,15). Including this report, 11 major QTL for cholelithiasis, named Lith1 through Lith11 (11,(16)(17)(18)(19)(20), have been reported. Each gallstone-susceptible inbred mouse strain carries only a subset (21) of all gallstone susceptibility alleles.…”

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Lith6

Lyons

Wittenburg

et al. 2003

Journal of Lipid Research

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A complex genetic basis determines the individual predisposition to develop cholesterol gallstones in response to environmental factors. We employed quantitative trait locus/loci (QTL) analyses of an intercross between inbred strains CAST/Ei (susceptible) and DBA/2J (resistant) to determine the subset of gallstone susceptibility ( Lith ) genes these strains possess. Parental and first filial generation mice of both genders and male intercross offspring were evaluated for gallstone formation after feeding a lithogenic diet. Linkage analysis was performed using a form of multiple interval mapping. One significant QTL colocalized with Lith1 [chromosome (chr) 2, 50 cM], a locus identified previously. Significantly, new QTL were detected and named Lith10 (chr 6, 4 cM), Lith6 (chr 6, 54 cM), and Lith11 (chr 8, 58 cM).Statistical and genetic analyses suggest that Lith6 comprises two QTL in close proximity. Our molecular and genetic data support the candidacy of peroxisome proliferator-activated receptor ␥ ( Pparg) and Slc21a1 , encoding Pparg , and the basolateral bile acid transporter SLC21A1 ( Slc21a1 / Oatp1 ), respectively, as genes underlying Studies of model (1-3), animal (4-6), and human biles (7-9) have greatly contributed to the elucidation of the pathophysiology of cholesterol gallstone formation (cholelithiasis). Investigation of both human (10) and mouse models (11) demonstrated that a complex genetic basis determines the individual predisposition to develop cholesterol gallstones in response to environmental factors (12). Advancement of our understanding of cholesterol homeostasis and of the mechanisms of bile formation enables us to identify the primary genetic determinants of cholesterol gallstone formation (13) and may lead to improved management and ultimately prevention of this prevalent and costly disorder (14). To this end, we employed quantitative trait locus/loci (QTL) analysis to define genomic regions associated with cholelithiasis in inbred mice. Our ultimate goal is to identify genes that carry polymorphisms determining cholesterol gallstone susceptibility (i.e., Lith genes) (13,15). Including this report, 11 major QTL for cholelithiasis, named Lith1 through Lith11 (11,(16)(17)(18)(19)(20), have been reported. Each gallstone-susceptible inbred mouse strain carries only a subset (21) of all gallstone susceptibility alleles. Therefore, to confirm loci from previous studies and to identify the entire ensemble of Lith loci in inbred mice, we are conducting a further series of QTL crosses between cholesterol gallstone-susceptible and -resistant inbred mouse strains that were selected on the basis of a large strain survey (22).Abbreviations: Abcb11 , bile salt export pump ( Bsep ); Apobec1 , apolipoprotein B mRNA editing complex 1; CAST, CAST/Ei; Cav , caveolin; Cav2 , caveolin 2; Cftr , cystic fibrosis transmembrane conductance regulator; ChMC, cholesterol monohydrate crystal; chr, chromosome; CI, confidence interval; CSI, cholesterol saturation index; Cyp7a1 /CYP7A1, cholesterol 7 ␣ -hydr...

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Section: Qtl Analysessupporting

confidence: 83%

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confidence: 99%

Lith6

Lyons

Wittenburg

et al. 2003

Journal of Lipid Research

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“…Inbred mouse strains that differ in their genetic susceptibility for cholesterol gallstone formation have been employed in genome-wide scans to identify a major lithogenic locus (Lith1) on mouse chromosome 2 (26). Interestingly, the Abcb11 gene maps to the Lith1 locus (24,25) and, given its physiologic function and the physical-chemical mechanisms of cholesterol gallstone formation, has been a candidate gene for Lith1 (40).…”

Section: Abcb11 Overexpression Alters Hepatic Lipid Metabolismmentioning

confidence: 99%

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Figge

Lammert

Paigen

et al. 2004

Journal of Biological Chemistry

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Abcb11 encodes for the liver bile salt export pump, which is rate-limiting for hepatobiliary bile salt secretion. We employed transthyretin-Abcb11 and BACAbcb11 transgenes to develop mice overexpressing the bile salt export pump in the liver. The mice manifest increases in bile flow and biliary secretion of bile salts, phosphatidylcholine, and cholesterol. Hepatic gene expression of cholesterol 7␣-hydroxylase and ileal expression of the apical sodium bile salt transporter are markedly reduced, whereas gene expression of targets of the nuclear bile salt receptor FXR (ileal lipid-binding protein, short heterodimer partner (SHP) is increased. Because these changes in gene expression are associated with an increased overall hydrophobicity of the bile salt pool and a 4-fold increase of the FXR ligand taurodeoxycholate, they reflect bile salt-mediated regulation of FXR and SHP target genes. Despite the increased biliary secretion of bile salts, fecal bile salt excretion is unchanged, suggestive of an enhanced enterohepatic cycling of bile salts. Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls. We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression. Because these mice are resistant to hepatic lipid accumulation, regulation of Abcb11 may be important for the pathogenesis and treatment of steatohepatitis.

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“…2,3 Compared with other animals species, [4][5][6] inbred strains of mice allow rigorous genetic control within a strain, yet genetic variance between strains, thereby offering the possibility to dissect the genetics of complex disease pathways. In C57L mice, 2 candidate Lith genes 7 for gallstone susceptibility have been identified on chromosomes 2 and 19. They may be identical with a canalicular bile acid export pump and the multidrug resistance-associated protein 2 regulating the bile-acid independent bile flow.…”

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Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi

Fuchs¹,

Ivandic

Müller³

et al. 2001

Hepatology

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Enhanced hepatocellular trafficking of cholesterol to the bile canaliculus and cholesterol hypersecretion appears critical for gallstone formation. Therefore, we studied in more detail the hepatic cholesterol transport pathways in a mouse model of cholesterol gallstone disease. Biliary lipid secretion rates, plasma lipoprotein levels, hepatic expression of lipoprotein receptors, lipid regulatory enzymes, and putative cholesterol transporting proteins were analyzed in gallstone-susceptible C57L/J and gallstone-resistant AKR/J mice, which were fed a lithogenic diet. Biliary cholesterol hypersecretion in C57L mice was associated with decreased plasma high-density lipoprotein (HDL) cholesterol levels and significant hepatic induction of the HDL receptor (SRBI) and cholesteryl ester hydrolase. In response to the lithogenic diet, fatty-acid binding protein of liver (FABPL) was markedly induced in both mouse strains. Caveolin 1 was elevated only in plasma membranes of gallstone-susceptible C57L mice, which also failed to down-regulate cholesterol synthesis. These data suggest a role of the reverse cholesterol transport pathway for genetically determined gallstone susceptibility in the mouse. (HEPATOLOGY 2001;33: 1451-1459.)

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Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice

Cited by 73 publications

References 35 publications

Lith6

Lith6

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi

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