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Microarray analysis of hepatic gene expression in gallstone-susceptible and gallstone-resistant mice

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Abstract

Cholesterol gallstone disease affects 40 million Americans, and evidence indicates that there is a genetic component to human gallstone disease. In a mouse model of gallstone formation, where mice are fed a lithogenic diet, QTL analysis has been employed to identify the Lith 1 locus on Chromosome (Chr) 2. In order to identify genes in which the difference in expression is independent of factors other than strain-specific genotype, we employed microarray analysis of hepatic gene expression in gallstone-susceptible (C57L/J) and gallstone-resistant (AKR/J) mice. We observed 57 genes with consistent differential expression between C57L/J and AKR/J mice, including many cytochrome, antioxidant, and lipid peroxidation genes. Analysis of differentially expressed genes identified numerous genes involved in fatty acid metabolism. Northern analysis of selected lipid metabolic genes further confirmed the strain-specific differential expression. Literature searches of common regulatory elements within antioxidant systems identified the nuclear transcription factor Nrf2, which maps to the Lith 1 loci. Hepatic Nrf2 gene and protein expression is also increased in strain AKR/J, compared with C57L/J mice, identifying Nrf2 as a putative Lith 1 gallstone gene. These data indicate that microarray analysis may complement QTL analysis to identify systems of regulation and genotypic differences responsible for polygenic diseases.

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References

  1. A Attili et al. (1997) ArticleTitleFactors associated with gallstone disease in the MICOL experience. Multicenter italian study on epidemiology of cholelithiasis. Hepatology 26 809–818 Occurrence Handle1:STN:280:ByiH28npsFM%3D Occurrence Handle9328297

    CAS  PubMed  Google Scholar 

  2. G Bouchard et al. (1999) ArticleTitleHigh-resolution maps of the murine chromosome. Mamm Genome 10 1070–1074 Occurrence Handle10.1007/s003359901163 Occurrence Handle1:CAS:528:DyaK1MXns1Srtbs%3D Occurrence Handle10556425

    Article  CAS  PubMed  Google Scholar 

  3. JD Buxbaum et al. (2002) ArticleTitlePharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Front Biosci 7 50–59

    Google Scholar 

  4. M Coggan et al. (1998) ArticleTitleStructure and organization of the human theta-class glutathione S-transferase and D-dopachrome tautomerase gene complex. Biochem J 334 617–623 Occurrence Handle1:CAS:528:DyaK1cXmsVKhu7k%3D Occurrence Handle9729470

    CAS  PubMed  Google Scholar 

  5. RH Dowling (2000) ArticleTitleReview: pathogenesis of gallstones. Aliment Pharmacol Ther 14S2 39–47 Occurrence Handle10.1046/j.1365-2036.2000.014s2039.x

    Article  Google Scholar 

  6. MI Eder et al. (1996) ArticleTitleReactive oxygen metabolites promote cholesterol crystal formation in model bile: role of lipid peroxidation. Free Radic Biol Med 20 743–749 Occurrence Handle10.1016/0891-5849(95)02154-X Occurrence Handle1:CAS:528:DyaK28XisVWjurY%3D Occurrence Handle8721618

    Article  CAS  PubMed  Google Scholar 

  7. J Feher et al. (1998) ArticleTitleBlazovics A. Oxidative stress in the liver and biliary tract diseases. Scand J Gastroenterol Suppl. 228 38–46 Occurrence Handle10.1080/003655298750026543 Occurrence Handle1:STN:280:DyaK1M%2FotlSjsg%3D%3D Occurrence Handle9867111

    Article  CAS  PubMed  Google Scholar 

  8. M Fuchs et al. (2001) ArticleTitleBiliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI. Hepatology 3 1451–1459 Occurrence Handle10.1053/jhep.2001.24373

    Article  Google Scholar 

  9. RM Green D Beier JL Gollan (1996) ArticleTitleRegulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology 111 193–198 Occurrence Handle1:CAS:528:DyaK28XkslWqur4%3D Occurrence Handle8698199

    CAS  PubMed  Google Scholar 

  10. U Gustafsson et al. (1997) ArticleTitleThe effect of vitamin C in high doses on plasma and biliary lipid composition in patients with cholesterol gallstones: prolongation of the nucleation time. Eur J Clin Invest 27 387–391 Occurrence Handle1:CAS:528:DyaK2sXjvVOktLs%3D Occurrence Handle9179545

    CAS  PubMed  Google Scholar 

  11. DE Johnston MM Kaplan (1993) ArticleTitlePathogenesis and treatment of gallstones. N Engl J Med 328 412–421 Occurrence Handle10.1056/NEJM199302113280608 Occurrence Handle1:STN:280:ByyC3szitlA%3D Occurrence Handle8421460

    Article  CAS  PubMed  Google Scholar 

  12. MM Kesavulu et al. (2002) ArticleTitleEffect of omega-3 fatty acids on lipid peroxidation and antioxidant enzyme status in type 2 diabetic patients. Diabetes Metab 28 20–26 Occurrence Handle1:CAS:528:DC%2BD38XivVGrt7o%3D Occurrence Handle11938024

    CAS  PubMed  Google Scholar 

  13. B Khanuja et al. (1995) ArticleTitleLith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci USA 92 7729–7733 Occurrence Handle1:CAS:528:DyaK2MXnsFOnsLc%3D Occurrence Handle7644485

    CAS  PubMed  Google Scholar 

  14. AR Koudinov et al. (2002) ArticleTitleCholesterol and Alzheimer’s disease: is there a link?. Neurology 58 1135

    Google Scholar 

  15. MK Kwak et al. (2001) ArticleTitleRole of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med 7 135–145 Occurrence Handle1:CAS:528:DC%2BD3MXitlKms7g%3D Occurrence Handle11471548

    CAS  PubMed  Google Scholar 

  16. F Lammert et al. (1999) ArticleTitlePhenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes. J Lipid Res 40 2080–2090 Occurrence Handle1:CAS:528:DyaK1MXnt1GrsrY%3D Occurrence Handle10553011

    CAS  PubMed  Google Scholar 

  17. F Lammert MC Carey B Paigen (2001) ArticleTitleChromosomal organization of candidate genes involved in gallstone formation: a murine gallstone map. Gastroenterology 120 221–238 Occurrence Handle1:CAS:528:DC%2BD3MXoslGjtA%3D%3D Occurrence Handle11208732

    CAS  PubMed  Google Scholar 

  18. WW LaMorte ML Booker S Kay (1998) ArticleTitleDeterminants of the selection of phosphatidylcholine molecular species for secretion into bile in the rat. Hepatology 28 631–637 Occurrence Handle10.1016/S0168-8278(98)80287-0 Occurrence Handle1:CAS:528:DyaK1cXlvVyit74%3D Occurrence Handle9731551

    Article  CAS  PubMed  Google Scholar 

  19. MA Leo SI Aleynik JH Siegel FE Kasmin MK Aleynik CS Lieber (1997) ArticleTitle. Am J Gastroenterol 92 2069–2072 Occurrence Handle1:STN:280:DyaK1c%2Fis1Giug%3D%3D Occurrence Handle9362195

    CAS  PubMed  Google Scholar 

  20. S Leutner et al. (2000) ArticleTitleReduced antioxidant enzyme activity in brains of mice transgenic for human presenilin-1 with single or multiple mutations. Neurosci Lett 292 87–90 Occurrence Handle10.1016/S0304-3940(00)01449-X Occurrence Handle1:CAS:528:DC%2BD3cXms1Wks7o%3D Occurrence Handle10998555

    Article  CAS  PubMed  Google Scholar 

  21. S Melov et al. (1999) ArticleTitleMitochondrial disease in superoxide dismutase 2 mutant mice. Proc Natl AcadSci USA 96 846–851 Occurrence Handle10.1073/pnas.96.3.846 Occurrence Handle1:CAS:528:DyaK1MXpvFWrug%3D%3D

    Article  CAS  Google Scholar 

  22. A Moschetta GP vanBerge-Henegouwen P Portincasa G Palasciano KJ van Erpecum (2001) ArticleTitleCholesterol crystallization in model biles: effects of bile salt and phospholipid species composition. J Lipid Res 42 1273–1281 Occurrence Handle1:CAS:528:DC%2BD3MXlvFeksL0%3D Occurrence Handle11483629

    CAS  PubMed  Google Scholar 

  23. O Muller et al. (2002) ArticleTitleExpression of liver plasma membrane transporters in gallstone-susceptible and gallstone-resistant mice. Biochem J 361 673–679 Occurrence Handle10.1042/0264-6021:3610673 Occurrence Handle1:CAS:528:DC%2BD38XhslOqt7k%3D Occurrence Handle11802798

    Article  CAS  PubMed  Google Scholar 

  24. B Paigen et al. (2000) ArticleTitleQuantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice. Physiol Genomics 4 59–65 Occurrence Handle1:CAS:528:DC%2BD3cXoslektrc%3D Occurrence Handle11074014

    CAS  PubMed  Google Scholar 

  25. MA Pappolla et al. (2001) ArticleTitleInduction of NADPH cytochrome P450 reductase by the Alzheimer beta-protein. Amyloid as a “foreign body”. J Neurochem 78 121–128 Occurrence Handle10.1046/j.1471-4159.2001.00379.x Occurrence Handle1:CAS:528:DC%2BD3MXltVymu7g%3D Occurrence Handle11432979

    Article  CAS  PubMed  Google Scholar 

  26. R Reiter et al. (2001) ArticleTitleCholelithiasis, oxidative stress, and melatonin. J Pineal Res 30 127–128 Occurrence Handle1:CAS:528:DC%2BD3MXhs1Shtbg%3D Occurrence Handle11270480

    CAS  PubMed  Google Scholar 

  27. A Rigotti et al. (2002) ArticleTitleHDL receptor SR-BI and cholesterol gallstones. Hepatology 35 240–242 Occurrence Handle11786985

    PubMed  Google Scholar 

  28. C Sama et al. (1990) ArticleTitleEpidemiology and natural history of gallstone disease. Semin Liver Dis 10 149–158 Occurrence Handle1:STN:280:By6D3Mblt1Q%3D

    CAS  Google Scholar 

  29. FS Shie et al. (2002) ArticleTitleDiet-induced hypercholesterolemia enhances brain Abeta accumulation in transgenic mice. Neuroreport 13 455–459 Occurrence Handle1:CAS:528:DC%2BD38XnsFKku70%3D Occurrence Handle11930160

    CAS  PubMed  Google Scholar 

  30. VK Shukla et al. (1994) ArticleTitleLipid peroxidation product in bile from patients with carcinoma of the gallbladder: a preliminary study. J Surg Oncol 56 258–262 Occurrence Handle1:STN:280:ByuA3srjtVM%3D Occurrence Handle8057656

    CAS  PubMed  Google Scholar 

  31. T Siddique et al. (1996) ArticleTitleMolecular genetic basis of familial ALS. Neurology 47 S27–S34 Occurrence Handle1:CAS:528:DyaK28XmsVejtr4%3D Occurrence Handle8858048

    CAS  PubMed  Google Scholar 

  32. JA Simon ES Hudes (1998) ArticleTitleSerum ascorbic acid and other correlates of gallbladder disease among US adults. Am J Public Health 88 1208–1212 Occurrence Handle1:STN:280:DyaK1czmslCksA%3D%3D Occurrence Handle9702150

    CAS  PubMed  Google Scholar 

  33. RK Thimmulappa et al. (2002) ArticleTitleIdentification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62 5196–5203 Occurrence Handle1:CAS:528:DC%2BD38Xnt1yns7Y%3D Occurrence Handle12234984

    CAS  PubMed  Google Scholar 

  34. HV Worthington LP Hunt RF McCloy I Maclennan JM Braganza (1997) ArticleTitleA pilot study of antioxidant intake in patients with cholesterol gallstones. Nutrition 13 118–1127 Occurrence Handle10.1016/S0899-9007(96)00385-1 Occurrence Handle1:STN:280:ByiB28%2Fms10%3D Occurrence Handle9106789

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health grants DK-59580, HD-40027, and a Veteran’s Administration Merit Review Award (R.M. Green).

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Authors and Affiliations

  1. Center for Genetic Medicine, Northwestern University, Chicago, IL, USA

    Patricia A. Dyck

  2. Department of Computer Science, Northwestern University, Chicago, IL, USA

    Patricia A. Dyck

  3. Department of Medicine and Division of Hepatology, Northwestern University Feinberg School of Medicine, Searle 10-541, 303 E. Chicago Avenue, Chicago, IL 60611, USA

    Farzana Hoda, Elizabeth S. Osmer & Richard M. Green

  4. VAMC-Lakeside Division, Chicago, IL, USA

    Richard M. Green

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  1. Patricia A. Dyck
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  2. Farzana Hoda
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Correspondence to Richard M. Green.

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Dyck, P.A., Hoda, F., Osmer, E.S. et al. Microarray analysis of hepatic gene expression in gallstone-susceptible and gallstone-resistant mice . Mamm Genome 14, 601–610 (2003). https://doi.org/10.1007/s00335-003-2269-9

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  • DOI: https://doi.org/10.1007/s00335-003-2269-9

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