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J Clin Invest. Mar 15, 1997; 99(6): 1406–1419.
PMCID: PMC507957

Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism.


Inbred strains of mice differ in susceptibility to atherogenesis when challenged with a high fat, high cholesterol diet containing 0.5% cholic acid. Studies of recombinant inbred (RI) strains derived from the susceptible strain C57BL/6J (B6) and the resistant strains C3H/HeJ (C3H) and BALB/cJ have revealed an association between fatty streak lesion size and a decrease in high density lipoprotein (HDL) levels on the diet. To better understand the genetic factors contributing to HDL metabolism and atherogenesis in response to the diet, we studied mice derived from an intercross between B6 and C3H using a complete linkage map approach. A total of 185 female progeny were typed for 134 genetic markers spanning the mouse genome, resulting in an average interval of about 10 cM between markers. A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on both the chow and the atherogenic diets, but this locus did not contribute to the decrease in HDL-cholesterol in response to the diet. At least three distinct genetic loci, on chromosomes 3, 5, and 11, exhibited evidence of linkage to a decrease in HDL-cholesterol after a dietary challenge. Since a bile acid (cholic acid) is required for the diet induced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression. Whereas B6 mice exhibited a large decrease in C7AH mRNA levels in response to the diet, C3H showed an increase. Among the intercross mice, multiple loci contributed to the regulation of C7AH mRNA levels in response to the diet, the most notable of which coincided with the loci on chromosomes 3, 5, and 11 controlling HDL levels in response to the diet. None of these loci were linked to the C7AH structural gene which we mapped to proximal chromosome 4. These studies reveal coordinate regulation of C7AH expression and HDL levels, and they indicate that the genetic factors controlling HDL levels are more complex than previously suggested by studies of RI strains. Furthermore, we observed that two of the loci for C7AH expression contributed to differences in gallstone formation between these strains.

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Selected References

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  • Paigen B, Mitchell D, Reue K, Morrow A, Lusis AJ, LeBoeuf RC. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3763–3767. [PMC free article] [PubMed]
  • Paigen B, Ishida BY, Verstuyft J, Winters RB, Albee D. Atherosclerosis susceptibility differences among progenitors of recombinant inbred strains of mice. Arteriosclerosis. 1990 Mar-Apr;10(2):316–323. [PubMed]
  • Stewart-Phillips JL, Lough J, Skamene E. ATH-3, a new gene for atherosclerosis in the mouse. Clin Invest Med. 1989 Apr;12(2):121–126. [PubMed]
  • Nishina PM, Wang J, Toyofuku W, Kuypers FA, Ishida BY, Paigen B. Atherosclerosis and plasma and liver lipids in nine inbred strains of mice. Lipids. 1993 Jul;28(7):599–605. [PubMed]
  • Paigen B. Genetics of responsiveness to high-fat and high-cholesterol diets in the mouse. Am J Clin Nutr. 1995 Aug;62(2):458S–462S. [PubMed]
  • LeBoeuf RC, Doolittle MH, Montcalm A, Martin DC, Reue K, Lusis AJ. Phenotypic characterization of the Ath-1 gene controlling high density lipoprotein levels and susceptibility to atherosclerosis. J Lipid Res. 1990 Jan;31(1):91–101. [PubMed]
  • Purcell-Huynh DA, Weinreb A, Castellani LW, Mehrabian M, Doolittle MH, Lusis AJ. Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. J Clin Invest. 1995 Oct;96(4):1845–1858. [PMC free article] [PubMed]
  • Jelinek DF, Andersson S, Slaughter CA, Russell DW. Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. J Biol Chem. 1990 May 15;265(14):8190–8197. [PubMed]
  • Wei JS, Huang HM, Shyu WC, Wu CS. Simple enzymatic determination of total cholesterol in gallstones. Clin Chem. 1989 Nov;35(11):2247–2249. [PubMed]
  • Warden CH, Fisler JS, Shoemaker SM, Wen PZ, Svenson KL, Pace MJ, Lusis AJ. Identification of four chromosomal loci determining obesity in a multifactorial mouse model. J Clin Invest. 1995 Apr;95(4):1545–1552. [PMC free article] [PubMed]
  • Dietrich W, Katz H, Lincoln SE, Shin HS, Friedman J, Dracopoli NC, Lander ES. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992 Jun;131(2):423–447. [PMC free article] [PubMed]
  • Ivandic BT, Qiao JH, Machleder D, Liao F, Drake TA, Lusis AJ. A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5483–5488. [PMC free article] [PubMed]
  • Manly KF. A Macintosh program for storage and analysis of experimental genetic mapping data. Mamm Genome. 1993;4(6):303–313. [PubMed]
  • Lander ES, Green P, Abrahamson J, Barlow A, Daly MJ, Lincoln SE, Newberg LA, Newburg L. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics. 1987 Oct;1(2):174–181. [PubMed]
  • Churchill GA, Doerge RW. Empirical threshold values for quantitative trait mapping. Genetics. 1994 Nov;138(3):963–971. [PMC free article] [PubMed]
  • Welch CL, Xia YR, Shechter I, Farese R, Mehrabian M, Mehdizadeh S, Warden CH, Lusis AJ. Genetic regulation of cholesterol homeostasis: chromosomal organization of candidate genes. J Lipid Res. 1996 Jul;37(7):1406–1421. [PubMed]
  • Mehrabian M, Qiao JH, Hyman R, Ruddle D, Laughton C, Lusis AJ. Influence of the apoA-II gene locus on HDL levels and fatty streak development in mice. Arterioscler Thromb. 1993 Jan;13(1):1–10. [PubMed]
  • Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. [PubMed]
  • Doolittle MH, LeBoeuf RC, Warden CH, Bee LM, Lusis AJ. A polymorphism affecting apolipoprotein A-II translational efficiency determines high density lipoprotein size and composition. J Biol Chem. 1990 Sep 25;265(27):16380–16388. [PubMed]
  • Warden CH, Hedrick CC, Qiao JH, Castellani LW, Lusis AJ. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science. 1993 Jul 23;261(5120):469–472. [PubMed]
  • Bain PA, Meisler MH, Taylor BA, Payne AH. The genes encoding gonadal and nongonadal forms of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase are closely linked on mouse chromosome 3. Genomics. 1993 Apr;16(1):219–223. [PubMed]
  • McBride MW, Russell AJ, Vass K, Forster V, Burridge SM, Morrison N, Boyd E, Ponder BA, Sutcliffe RG. New members of the 3 beta-hydroxysteroid dehydrogenase gene family. Mol Cell Probes. 1995 Apr;9(2):121–128. [PubMed]
  • Chiang JY, Stroup D. Identification and characterization of a putative bile acid-responsive element in cholesterol 7 alpha-hydroxylase gene promoter. J Biol Chem. 1994 Jul 1;269(26):17502–17507. [PubMed]
  • Cohen JC, Cali JJ, Jelinek DF, Mehrabian M, Sparkes RS, Lusis AJ, Russell DW, Hobbs HH. Cloning of the human cholesterol 7 alpha-hydroxylase gene (CYP7) and localization to chromosome 8q11-q12. Genomics. 1992 Sep;14(1):153–161. [PubMed]
  • Dueland S, Drisko J, Graf L, Machleder D, Lusis AJ, Davis RA. Effect of dietary cholesterol and taurocholate on cholesterol 7 alpha-hydroxylase and hepatic LDL receptors in inbred mice. J Lipid Res. 1993 Jun;34(6):923–931. [PubMed]
  • Lusis AJ, Taylor BA, Wangenstein RW, LeBoeuf RC. Genetic control of lipid transport in mice. II. Genes controlling structure of high density lipoproteins. J Biol Chem. 1983 Apr 25;258(8):5071–5078. [PubMed]
  • Hedrick CC, Castellani LW, Warden CH, Puppione DL, Lusis AJ. Influence of mouse apolipoprotein A-II on plasma lipoproteins in transgenic mice. J Biol Chem. 1993 Sep 25;268(27):20676–20682. [PubMed]
  • Liao F, Andalibi A, Qiao JH, Allayee H, Fogelman AM, Lusis AJ. Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J Clin Invest. 1994 Aug;94(2):877–884. [PMC free article] [PubMed]
  • Hyman RW, Frank S, Warden CH, Daluiski A, Heller R, Lusis AJ. Quantitative trait locus analysis of susceptibility to diet-induced atherosclerosis in recombinant inbred mice. Biochem Genet. 1994 Dec;32(11-12):397–407. [PubMed]
  • Shih DM, Gu L, Hama S, Xia YR, Navab M, Fogelman AM, Lusis AJ. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest. 1996 Apr 1;97(7):1630–1639. [PMC free article] [PubMed]
  • Hardon EM, Frain M, Paonessa G, Cortese R. Two distinct factors interact with the promoter regions of several liver-specific genes. EMBO J. 1988 Jun;7(6):1711–1719. [PMC free article] [PubMed]
  • Mietus-Snyder M, Sladek FM, Ginsburg GS, Kuo CF, Ladias JA, Darnell JE, Jr, Karathanasis SK. Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol. 1992 Apr;12(4):1708–1718. [PMC free article] [PubMed]
  • Chan J, Nakabayashi H, Wong NC. HNF-4 increases activity of the rat Apo A1 gene. Nucleic Acids Res. 1993 Mar 11;21(5):1205–1211. [PMC free article] [PubMed]
  • Zhong W, Mirkovitch J, Darnell JE., Jr Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression. Mol Cell Biol. 1994 Nov;14(11):7276–7284. [PMC free article] [PubMed]
  • Poorman JA, Buck RA, Smith SA, Overturf ML, Loose-Mitchell DS. Bile acid excretion and cholesterol 7 alpha-hydroxylase expression in hypercholesterolemia-resistant rabbits. J Lipid Res. 1993 Oct;34(10):1675–1685. [PubMed]
  • Overturf ML, Smith SA, Gotto AM, Jr, Morrisett JD, Tewson T, Poorman J, Loose-Mitchell DS. Dietary cholesterol absorption, and sterol and bile acid excretion in hypercholesterolemia-resistant white rabbits. J Lipid Res. 1990 Nov;31(11):2019–2027. [PubMed]
  • Loose-Mitchell DS, Poorman JA, Smith SA, Overturf ML, Morrisett JD, Gotto AM, Jr, Soma MR. Cholesterol metabolism in hypercholesterolemia-resistant rabbits. Atherosclerosis. 1991 Apr;87(2-3):169–181. [PubMed]
  • Müller KR, Li JR, Dinh DM, Subbiah MT. The characteristics and metabolism of a genetically hypercholesterolemic strain of rats (RICO). Biochim Biophys Acta. 1979 Aug 30;574(2):334–343. [PubMed]
  • Spady DK, Cuthbert JA, Willard MN, Meidell RS. Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol. J Clin Invest. 1995 Aug;96(2):700–709. [PMC free article] [PubMed]
  • Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis. 1985 Oct;57(1):65–73. [PubMed]
  • Carrella M, Ericsson S, Del Piano C, Angelin B, Einarsson K. Effect of cholestyramine treatment on biliary lipid secretion rates in normolipidaemic men. J Intern Med. 1991 Mar;229(3):241–246. [PubMed]
  • Einarsson K, Ericsson S, Ewerth S, Reihnér E, Rudling M, Ståhlberg D, Angelin B. Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol. 1991;40 (Suppl 1):S53–S58. [PubMed]
  • Reihnér E, Angelin B, Rudling M, Ewerth S, Björkhem I, Einarsson K. Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients. J Lipid Res. 1990 Dec;31(12):2219–2226. [PubMed]
  • Heuman DM, Vlahcevic ZR, Bailey ML, Hylemon PB. Regulation of bile acid synthesis. II. Effect of bile acid feeding on enzymes regulating hepatic cholesterol and bile acid synthesis in the rat. Hepatology. 1988 Jul-Aug;8(4):892–897. [PubMed]
  • Hwa JJ, Zollman S, Warden CH, Taylor BA, Edwards PA, Fogelman AM, Lusis AJ. Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. J Lipid Res. 1992 May;33(5):711–725. [PubMed]
  • Ishibashi S, Schwarz M, Frykman PK, Herz J, Russell DW. Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation. J Biol Chem. 1996 Jul 26;271(30):18017–18023. [PubMed]
  • Schwarz M, Lund EG, Setchell KD, Kayden HJ, Zerwekh JE, Björkhem I, Herz J, Russell DW. Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase. J Biol Chem. 1996 Jul 26;271(30):18024–18031. [PubMed]
  • Nishina PM, Verstuyft J, Paigen B. Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J Lipid Res. 1990 May;31(5):859–869. [PubMed]
  • Chijiiwa K, Hirota I, Noshiro H. High vesicular cholesterol and protein in bile are associated with formation of cholesterol but not pigment gallstones. Dig Dis Sci. 1993 Jan;38(1):161–166. [PubMed]
  • Heaton KW, Read AE. Gall stones in patients with disorders of the terminal ileum and disturbed bile salt metabolism. Br Med J. 1969 Aug 30;3(5669):494–496. [PMC free article] [PubMed]
  • Nestel PJ, Poyser A. Changes in cholesterol synthesis and excretion when cholesterol intake is increased. Metabolism. 1976 Dec;25(12):1591–1599. [PubMed]
  • Lindblad L, Lundholm K, Scherstén T. Influence of cholic and chenodeoxycholic acid on biliary cholesterol secretion in man. Eur J Clin Invest. 1977 Oct;7(5):383–388. [PubMed]
  • Ito T, Kawata S, Imai Y, Kakimoto H, Trzaskos JM, Matsuzawa Y. Hepatic cholesterol metabolism in patients with cholesterol gallstones: enhanced intracellular transport of cholesterol. Gastroenterology. 1996 May;110(5):1619–1627. [PubMed]
  • Vlahcevic ZR, Bell CC, Jr, Buhac I, Farrar JT, Swell L. Diminished bile acid pool size in patients with gallstones. Gastroenterology. 1970 Aug;59(2):165–173. [PubMed]
  • Khanuja B, Cheah YC, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7729–7733. [PMC free article] [PubMed]

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