Description

Strain Information

Former Names B6;129X1(FVB)-Nr1h4tm1Gonz/J    (Changed: 07-AUG-08 ) B6;129X(FVB)-Nr1h4tm1Gonz/J    (Changed: 16-MAY-08 ) B6;129X(FVB)-Nr1h4tm1Gonz    (Changed: 15-DEC-04 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation [N2+F2N1p]F8 (04-DEC-07)   Donating Investigator Frank Gonzalez,   National Institutes of Health

Description
Mice that are homozygous for the targeted Nr1h4 allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No Nr1h4 protein product is detected in liver tissue although an aberrant transcript appears to be generated. Homozygous mice display a proatherogenic serum lipoprotein profile characterized by elevated levels of serum and hepatic cholesterol and triglycerides. Serum bile acids are also elevated. When fed a diet supplemented with 1% cholic acid, severe wasting, hypothermia and increased mortality is observed. Wildtype mice fed a similar diet display no ill effects. Levels of fecal bile excretion are reduced in homozygotes. This mutant mouse strain represents a model that may be useful in studies related to bile acid and lipid homeostasis.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt the exon encoding the ligand-binding domain (nts 1238-1779). A loxP site was placed 5' of the targeted exon. The neomycin resistance and thymidine kinase genes were flanked by loxP sites and placed 3' of the targeted exon. The construct was electroporated into 129X1/SvJ-derived embryonic stem (ES) cells from Genome Systems Inc. (St. Louis, MO). Correctly targeted ES cells were injected into C57BL/6N blastocysts. The resulting chimeric animals were crossed to female C57BL/6N mice. Progeny animals were mated with heterozygous transgenic mice expressing Cre recombinase (EIIA promoter) on a pure FVB background. Offspring bearing the recombined Nr1h4 allele, but not the Cre transgene were obtained.

Control Information

	Control
	None Available
Considerations for Choosing Controls

Related Strains

Strains carrying   Nr1h4^tm1Gonz allele

007214

B6.129X1(FVB)-Nr1h4tm1Gonz/J

View Strains carrying   Nr1h4^tm1Gonz     (1 strain)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Nr1h4^tm1Gonz/Nr1h4^tm1Gonz

        involves: C57BL/6N

• life span-post-weaning/aging
• abnormal induced morbidity/mortality (MGI Ref ID J:64792)
  • about 30% of mutants die by day 7 when placed on a 1% cholic acid diet
• growth/size phenotype
• weight loss (MGI Ref ID J:64792)
  • mutants on a 1% cholic acid diet exhibit a progressive decrease in body weight that results in about 1/3 of the initial body weight by day 5 of the diet
• cachexia (MGI Ref ID J:64792)
  • mutants on a 1% cholic acid diet exhibit severe wasting
• homeostasis/metabolism phenotype
• abnormal bile salt homeostasis (MGI Ref ID J:64792)
  • mutants on a regular diet and 1% cholic acid diet have fecal bile acid excretion about 2-fold and 4-fold, respectively, lower than in wild-type
  • mutants on a 1% cholic acid diet exhibit higher (7-fold) urinary bile acid excretion rates than wild-type on the same diet
• abnormal bile salt level (MGI Ref ID J:64792)
  • mutants on a regular diet exhibit an 8-fold increase in total serum bile acid concentration
  • mutants on a 1% cholic acid diet exhibit an 23-fold increase in total serum bile acid concentration
  • mutants on a regular or 1% cholic acid diet have lower bile acid pool (about by 2 fold) than wild-type
• decreased body temperature (MGI Ref ID J:64792)
  • mutants on a 1% cholic acid diet exhibit hypothermia
• increased cholesterol level (MGI Ref ID J:64792)
  • mutants on a 1% cholesterol diet show 1.4-fold greater hepatic cholesterol levels
• increased circulating cholesterol level (MGI Ref ID J:64792)
  • mutants on a regular diet or on a 1% cholesterol diet exhibit increased serum total cholesterol levels
• increased circulating phospholipid level (MGI Ref ID J:64792)
  • mutants on a regular diet or on a 1% cholesterol diet exhibit increased phospholipid levels
• increased triglyceride level (MGI Ref ID J:64792)
  • mutants on a regular diet show 2.2-fold greater hepatic triglyceride levels
  • mutants on a 1% cholesterol diet show 2.4-fold greater hepatic triglyceride levels
• increased circulating triglyceride level (MGI Ref ID J:64792)
  • mutants on a regular or a 1% cholesterol diet exhibit increased triglyceride levels
• liver/biliary system phenotype
• abnormal liver morphology (MGI Ref ID J:64792)
  • mutants on a 1% cholic acid diet exhibit liver lesions indicative of severe hepatotoxicity, with numerous vacuolated and necrotic cells
• hepatic steatosis (MGI Ref ID J:64792)
  • mutants on a regular diet or a 1% cholesterol diet exhibit more lipid containing vacuoles in the liver than wild-type

Nr1h4^tm1Gonz/Nr1h4^tm1Gonz

        involves: 129/Sv

• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype (MGI Ref ID J:118368)
  • normal plasma levels of testosterone

Nr1h4^tm1Gonz/Nr1h4^tm1Gonz

        involves: 129X1/SvJ

• liver/biliary system phenotype
• abnormal bile composition (MGI Ref ID J:129978)
  • the increase in the bile acid pool consists of increases in cholate and its derivates including taurocholic acid and taurodeoxycholic acid while other bile acids are found at normal levels
• homeostasis/metabolism phenotype
• increased bile salt level (MGI Ref ID J:129978)
  • serum bile acids are greatly elevated in these mice
  • total bile acid pool collected from liver, gallbladder and small intestine is almost 2.5-fold higher than in controls
  • the increases in the bile acid pool consist of increases in cholate and its derivates including taurocholic acid and taurodeoxycholic acid
• increased circulating cholesterol level (MGI Ref ID J:129978)
  • total cholesterol levels in serum are about double that found in wild-type mice
• increased circulating triglyceride level (MGI Ref ID J:129978)
  • serum triglyceride levels are significantly higher than in control mice

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Nr1h4^tm1Gonz related

Metabolism Research
Lipid Metabolism

Genes & Alleles

Gene & Allele Information

Allele Symbol		Nr1h4tm1Gonz
Allele Name		targeted mutation 1, Frank Gonzalez
Allele Type		Targeted (knock-out)
Common Name(s)		FXR/BAR -; FXR-; FXRalpha-; Fxrtm1Gonz;
Mutation Made By		Frank Gonzalez,   National Institutes of Health
Strain of Origin		129X1/SvJ
Gene Symbol and Name		Nr1h4, nuclear receptor subfamily 1, group H, member 4
Chromosome		10
Gene Common Name(s)		AI957360; BAR; FXR; Fxr; HRR-1; HRR1; MGC163445; MGC94878; RIP14; Rxrip14; expressed sequence AI957360; farnesoid X receptor; retinoid X receptor interacting protein 14;
General Note		The ES cell line was not specified, but was purchased from Genome Systems (St. Louis, MO). (Note added 7/26/01: Genome Systems was bought by Incyte.)
Molecular Note		Mice with a targeted deletion of the last exon encoding the ligand binding domain and all of the 3' untranslated region were produced as follows: A loxP site was inserted in the intron 5' to the last exon and a loxP-flanked neomycin cassette was inserted 3' to the last exon. After production of chimeric founder mice, F1 mice were mated to Tg(EIIa-Cre)1Lmgd mice to produce offspring that carried a recombined deletion of the last exon and neomycin cassette. No Nr1h4 protein product is detected in liver tissue from these null mice although an aberrant transcript appears to be generated. [MGI Ref ID J:64792]

Genotyping

Genotyping Information

Genotyping Protocols

Nr1h4^tm1Gonz, STD PCR, vers. 2

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Sinal CJ; Tohkin M; Miyata M; Ward JM; Lambert G; Gonzalez FJ. 2000. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis Cell 102(6):731-44. [PubMed: 11030617]  [MGI Ref ID J:64792]

Additional References

Nr1h4^tm1Gonz related

Boyer JL; Trauner M; Mennone A; Soroka CJ; Cai SY; Moustafa T; Zollner G; Lee JY; Ballatori N. 2006. Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol 290(6):G1124-30. [PubMed: 16423920]  [MGI Ref ID J:111085]

Cariou B; Bouchaert E; Abdelkarim M; Dumont J; Caron S; Fruchart JC; Burcelin R; Kuipers F; Staels B. 2007. FXR-deficiency confers increased susceptibility to torpor. FEBS Lett 581(27):5191-8. [PubMed: 17950284]  [MGI Ref ID J:127752]

Cariou B; van Harmelen K; Duran-Sandoval D; van Dijk T; Grefhorst A; Bouchaert E; Fruchart JC; Gonzalez FJ; Kuipers F; Staels B. 2005. Transient impairment of the adaptive response to fasting in FXR-deficient mice. FEBS Lett 579(19):4076-80. [PubMed: 16023103]  [MGI Ref ID J:100327]

Cariou B; van Harmelen K; Duran-Sandoval D; van Dijk TH; Grefhorst A; Abdelkarim M; Caron S; Torpier G; Fruchart JC; Gonzalez FJ; Kuipers F; Staels B. 2006. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281(16):11039-49. [PubMed: 16446356]  [MGI Ref ID J:110560]

Duran-Sandoval D; Cariou B; Percevault F; Hennuyer N; Grefhorst A; van Dijk TH; Gonzalez FJ; Fruchart JC; Kuipers F; Staels B. 2005. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem 280(33):29971-9. [PubMed: 15899888]  [MGI Ref ID J:101042]

Guo GL; Lambert G; Negishi M; Ward JM; Brewer HB Jr; Kliewer SA; Gonzalez FJ; Sinal CJ. 2003. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J Biol Chem 278(46):45062-71. [PubMed: 12923173]  [MGI Ref ID J:129256]

Guo GL; Santamarina-Fojo S; Akiyama TE; Amar MJ; Paigen BJ; Brewer B Jr; Gonzalez FJ. 2006. Effects of FXR in foam-cell formation and atherosclerosis development. Biochim Biophys Acta 1761(12):1401-9. [PubMed: 17110163]  [MGI Ref ID J:118172]

Gutierrez A; Ratliff EP; Andres AM; Huang X; McKeehan WL; Davis RA. 2006. Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4. Arterioscler Thromb Vasc Biol 26(2):301-6. [PubMed: 16284190]  [MGI Ref ID J:118817]

Hanniman EA; Lambert G; McCarthy TC; Sinal CJ. 2005. Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice. J Lipid Res 46(12):2595-604. [PubMed: 16186601]  [MGI Ref ID J:106149]

Houten SM; Volle DH; Cummins CL; Mangelsdorf DJ; Auwerx J. 2007. In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol Endocrinol 21(6):1312-23. [PubMed: 17426284]  [MGI Ref ID J:121836]

Huang W; Ma K; Zhang J; Qatanani M; Cuvillier J; Liu J; Dong B; Huang X; Moore DD. 2006. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312(5771):233-6. [PubMed: 16614213]  [MGI Ref ID J:108344]

Hubbert ML; Zhang Y; Lee FY; Edwards PA. 2007. Regulation of hepatic Insig-2 by the farnesoid X receptor. Mol Endocrinol 21(6):1359-69. [PubMed: 17440045]  [MGI Ref ID J:121842]

Inagaki T; Moschetta A; Lee YK; Peng L; Zhao G; Downes M; Yu RT; Shelton JM; Richardson JA; Repa JJ; Mangelsdorf DJ; Kliewer SA. 2006. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 103(10):3920-5. [PubMed: 16473946]  [MGI Ref ID J:107133]

Inoue J; Satoh S; Kita M; Nakahara M; Hachimura S; Miyata M; Nishimaki-Mogami T; Sato R. 2008. PPARalpha gene expression is up-regulated by LXR and PXR activators in the small intestine. Biochem Biophys Res Commun 371(4):675-8. [PubMed: 18448072]  [MGI Ref ID J:136213]

Jansen PL. 2007. Endogenous bile acids as carcinogens. J Hepatol 47(3):434-5. [PubMed: 17624466]  [MGI Ref ID J:126534]

Jung D; Mangelsdorf DJ; Meyer UA. 2006. Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 281(28):19081-91. [PubMed: 16682417]  [MGI Ref ID J:114858]

Kim I; Ahn SH; Inagaki T; Choi M; Ito S; Guo GL; Kliewer SA; Gonzalez FJ. 2007. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48(12):2664-72. [PubMed: 17720959]  [MGI Ref ID J:129978]

Kim I; Morimura K; Shah Y; Yang Q; Ward JM; Gonzalez FJ. 2007. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28(5):940-6. [PubMed: 17183066]  [MGI Ref ID J:121075]

Lambert G; Amar MJ; Guo G; Brewer HB Jr; Gonzalez FJ; Sinal CJ. 2003. The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis. J Biol Chem 278(4):2563-70. [PubMed: 12421815]  [MGI Ref ID J:81724]

Lee H; Hubbert ML; Osborne TF; Woodford K; Zerangue N; Edwards PA. 2007. Regulation of the sodium/sulfate co-transporter by farnesoid X receptor alpha. J Biol Chem 282(30):21653-61. [PubMed: 17545158]  [MGI Ref ID J:124601]

Lee H; Zhang Y; Lee FY; Nelson SF; Gonzalez FJ; Edwards PA. 2006. FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. J Lipid Res 47(1):201-14. [PubMed: 16251721]  [MGI Ref ID J:106031]

Li J; Pircher PC; Schulman IG; Westin SK. 2005. Regulation of complement C3 expression by the bile acid receptor FXR. J Biol Chem 280(9):7427-34. [PubMed: 15590640]  [MGI Ref ID J:105051]

Ma K; Saha PK; Chan L; Moore DD. 2006. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116(4):1102-9. [PubMed: 16557297]  [MGI Ref ID J:107809]

Marschall HU; Wagner M; Bodin K; Zollner G; Fickert P; Gumhold J; Silbert D; Fuchsbichler A; Sjovall J; Trauner M. 2006. Fxr(-/-) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. J Lipid Res 47(3):582-92. [PubMed: 16327028]  [MGI Ref ID J:107554]

Moschetta A; Bookout AL; Mangelsdorf DJ. 2004. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med 10(12):1352-8. [PubMed: 15558057]  [MGI Ref ID J:94664]

Ratliff EP; Gutierrez A; Davis RA. 2006. Transgenic expression of CYP7A1 in LDL receptor-deficient mice blocks diet-induced hypercholesterolemia. J Lipid Res 47(7):1513-20. [PubMed: 16609145]  [MGI Ref ID J:112052]

Rizzo G; Disante M; Mencarelli A; Renga B; Gioiello A; Pellicciari R; Fiorucci S. 2006. The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo. Mol Pharmacol 70(4):1164-73. [PubMed: 16778009]  [MGI Ref ID J:135714]

Shih DM; Kast-Woelbern HR; Wong J; Xia YR; Edwards PA; Lusis AJ. 2006. A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. J Lipid Res 47(2):384-92. [PubMed: 16269825]  [MGI Ref ID J:107566]

Stedman C; Liddle C; Coulter S; Sonoda J; Alvarez JG; Evans RM; Downes M. 2006. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A 103(30):11323-8. [PubMed: 16844773]  [MGI Ref ID J:111798]

Volle DH; Duggavathi R; Magnier BC; Houten SM; Cummins CL; Lobaccaro JM; Verhoeven G; Schoonjans K; Auwerx J. 2007. The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice. Genes Dev 21(3):303-15. [PubMed: 17289919]  [MGI Ref ID J:118368]

Wang YD; Yang F; Chen WD; Huang X; Lai L; Forman BM; Huang W. 2008. Farnesoid x receptor protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo. Mol Endocrinol 22(7):1622-32. [PubMed: 18436567]  [MGI Ref ID J:136910]

Yamamoto Y; Moore R; Hess HA; Guo GL; Gonzalez FJ; Korach KS; Maronpot RR; Negishi M. 2006. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. J Biol Chem 281(24):16625-31. [PubMed: 16606610]  [MGI Ref ID J:113721]

Yang F; Huang X; Yi T; Yen Y; Moore DD; Huang W. 2007. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67(3):863-7. [PubMed: 17283114]  [MGI Ref ID J:118204]

Yu L; Gupta S; Xu F; Liverman AD; Moschetta A; Mangelsdorf DJ; Repa JJ; Hobbs HH; Cohen JC. 2005. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem 280(10):8742-7. [PubMed: 15611112]  [MGI Ref ID J:128570]

Zhang Y; Castellani LW; Sinal CJ; Gonzalez FJ; Edwards PA. 2004. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 18(2):157-69. [PubMed: 14729567]  [MGI Ref ID J:87780]

Zhang Y; Lee FY; Barrera G; Lee H; Vales C; Gonzalez FJ; Willson TM; Edwards PA. 2006. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 103(4):1006-11. [PubMed: 16410358]  [MGI Ref ID J:105654]

Zhang Y; Wang X; Vales C; Lee FY; Lee H; Lusis AJ; Edwards PA. 2006. FXR deficiency causes reduced atherosclerosis in Ldlr-/- mice. Arterioscler Thromb Vasc Biol 26(10):2316-21. [PubMed: 16825595]  [MGI Ref ID J:128055]

Zollner G; Wagner M; Fickert P; Geier A; Fuchsbichler A; Silbert D; Gumhold J; Zatloukal K; Kaser A; Tilg H; Denk H; Trauner M. 2005. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver. Am J Physiol Gastrointest Liver Physiol 289(5):G798-805. [PubMed: 16002565]  [MGI Ref ID J:104772]

Zollner G; Wagner M; Moustafa T; Fickert P; Silbert D; Gumhold J; Fuchsbichler A; Halilbasic E; Denk H; Marschall HU; Trauner M. 2006. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol 290(5):G923-32. [PubMed: 16357057]  [MGI Ref ID J:111080]

van Erpecum KJ; Wang DQ; Moschetta A; Ferri D; Svelto M; Portincasa P; Hendrickx JJ; Schipper M; Calamita G. 2006. Gallbladder histopathology during murine gallstone formation: relation to motility and concentrating function. J Lipid Res 47(1):32-41. [PubMed: 16224116]  [MGI Ref ID J:106039]

Health & husbandry

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Animal Health Reports

Room Number           AX12

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Diet Information	LabDiet® 5K52/5K67

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Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	None Available
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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