Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice

Wittenburg, Henning; Lyons, Malcolm A.; Li, Renhua; Kurtz, Ulrike; Mössner, Joachim; Churchill, Gary A.; Carey, Martin C.; Paigen, Beverly

doi:10.1007/s00335-005-0006-2

Cited by 35 publications

(23 citation statements)

References 27 publications

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“…The susceptible allele was conferred by strain I [8]. This finding explains why Lith7 was not detected in another cross of strain P with the gallstone-resistant strain DBA/2J (D) [9]. We identified Nr1h4 as positional candidate gene for Lith7 and the results of genetic and molecular analyses in strains P and I were consistent with Nr1h4 underlying Lith7 [8].…”

Section: Introductionsupporting

confidence: 73%

“…Furthermore, we identified no expression or sequence differences of Nr1h3 among the three strains in our study, excluding variation in the response of the nuclear oxysterol receptor LXRa to cholesterol feeding as the underlying mechanism of differences in Cyp7a1 and Cyp8b1 expression. Cyp7a1 and Cyp8b1 map to chromosome 4 and chromosome 9, respectively, and both genomic regions do not contain Lith loci in the P · I and P · D QTL crosses [8,9]. Therefore, polymorphisms in these genes are unlikely to explain the observed expression differences.…”

Section: Discussionmentioning

confidence: 98%

“…In all three inbred mouse strains the 5 0 regions, individual exons, intron/exon splicing sites and the 3 0 untranslated region (UTR) of both Nr1h4 transcripts were sequenced following standard PCR of DNA fragments [16]. In addition, in all three inbred mouse strains overlapping fragments of Nr1h3 were sequenced following amplification of DNA or cDNA after reverse transcription [9]. To identify genetic variants of NR1H4 in humans, all exons including intron/exon splicing sites of both NR1H4 transcripts, the 5 0 region ($1500 bp upstream of the first transcription initiation site) and the 3 0 UTR were sequenced in DNA samples from 24 non-related Mexican subjects (12 with and 12 without gallstones).…”

Section: Sequencingmentioning

confidence: 99%

“…Livers from mouse strains I, P, and D were harvested at The Jackson Laboratory, Bar Harbor, ME, and previously employed for expression studies [9]. Male animals were fed a low-cholesterol (<0.02%) chow until 6-8 weeks of age, followed by a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butter fat [12] or chow for additional 4 weeks.…”

Section: Mice and Dietsmentioning

confidence: 99%

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Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans

Kovacs

Kress

Rocha

et al. 2008

Journal of Hepatology

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Section: Introductionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Sequencingmentioning

confidence: 99%

Section: Mice and Dietsmentioning

confidence: 99%

See 2 more Smart Citations

Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans

Kovacs

Kress

Rocha

et al. 2008

Journal of Hepatology

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“…There was also a tendency for reduced serum cholesterol in pair-fed mice, but it failed to reach statistical significance. FPLC analysis of pooled plasma indicates that the reduction in serum cholesterol concentrations in leptin-treated and pair-fed controls was confined to the low density lipoprotein-containing fractions (13)(14)(15)(16)(17)(18) and was slightly offset by modest increases in the high density lipoprotein-containing fractions (18 -22, Fig. 2C).…”

Section: Resultsmentioning

confidence: 99%

Defects in the Leptin Axis Reduce Abundance of the ABCG5-ABCG8 Sterol Transporter in Liver

Sabeva

Rouse

Graf

2007

Journal of Biological Chemistry

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ABGG5 (G5) and ABCG8 (G8) are ABC half-transporters that dimerize within the endoplasmic reticulum, traffic to the cell surface, and mediate cholesterol excretion into bile. Mice harboring defects in the leptin axis (db/db and ob/ob) have reduced biliary cholesterol concentrations. Rapid weight loss brought about by administration of leptin or dietary restriction increases biliary cholesterol excretion. We hypothesized that the reduction in biliary cholesterol in mice harboring defects in the leptin axis is associated with a reduction in G5G8 transporters and that levels of the transporter would increase with leptin administration and dietary restriction. We examined mRNA and protein levels for G5 and G8 in db/db and ob/ob mice. In both models G5 and G8 protein levels were reduced. In ob/ob mice, both leptin administration and dietary restriction increased G5 and G8 protein and biliary cholesterol concentrations. Finally, we examined the effects of tauroursodeoxycholate, which has been shown to increase biliary cholesterol excretion and function as a molecular chaperone. Tauroursodeoxycholate increased G5 and G8 protein and biliary cholesterol concentrations in both wild-type and db/db mice. Our results indicate that the mechanism for reduced biliary cholesterol excretion in db/db and ob/ob mice involves reductions in G5 and G8 protein levels and that this may occur at the level of G5G8 heterodimer assembly within the endoplasmic reticulum. ABCG5 (G5) and ABCG8 (G8) play a major role in the elimination of dietary and endogenously synthesized sterols in humans and mice (1-5). G5 and G8 are ATP binding cassette (ABC) 2 half-transporters that dimerize in the endoplasmic reticulum (ER) before trafficking of the functional G5G8 sterol transporter to the apical surface where it promotes the excretion of sterols from hepatocytes and enterocytes (3, 6 -8). In the liver, the G5G8 sterol transporter appears to be the major route for cholesterol excretion into bile. Mice deficient in G5, G8, or both transporters have 80 -90% reductions in biliary cholesterol concentrations (3-5). Conversely, expression of a human transgene in mice results in a 6 -8-fold increase in biliary cholesterol concentration and supersaturation of bile (7).In the absence of dietary or pharmacological perturbations, biliary cholesterol concentrations correlate with Abcg5/Abcg8 genocopy (9). Activation of the liver X receptor (LXR␣, NR1H3) by cholesterol feeding or administration of an agonist increases G5 and G8 mRNA as well as biliary cholesterol concentrations (10). In addition, these effects are absent in mice lacking LXR ␣/␤, suggesting that LXR is the principal regulator of G5 and G8 expression in response to dietary cholesterol (11). Although biliary cholesterol excretion generally correlates with expression levels of G5 and G8 mRNAs, exceptions include increases in biliary cholesterol excretion after treatment with diosgenin or tauroursodeoxycholate (TUDCA) and in liver transplant patients after surgery (12-14). The uncoupling of biliary chole...

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Genetics and Liver Diseases

Huang¹,

Cheung²,

Donaldson³

et al. 2007

Textbook of Hepatology

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Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice

Cited by 35 publications

References 27 publications

Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans

Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans

Defects in the Leptin Axis Reduce Abundance of the ABCG5-ABCG8 Sterol Transporter in Liver

Genetics and Liver Diseases

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