Overview

Also Known As:FXR/BAR-

Mice homozygous for this targeted mutant allele display a proatherogenic serum lipoprotein profile characterized by elevated levels of serum and hepatic cholesterol and triglycerides. This mutant mouse strain represents a model that may be useful in studies related to bile acid and lipid homeostasis.

Donating Investigator

IMR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation
	N11F8 (2019-07-12 00:00:00)

Nr1h4^tm1Gonz

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Nr1h4	nuclear receptor subfamily 1, group H, member 4

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Research Applications

Metabolism Research
Internal/Organ Research

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Base Price

Starting at:

$236.78 Domestic price for female 4-week

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Details

Detailed 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.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

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. The mice were then backcrossed to C57BL/6J for 5 generations.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

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):731-44PubMed: 11030617 MGI: J:64792

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Genetics

Nr1h4^tm1Gonz

Allele Symbol: Nr1h4^tm1Gonz

Allele Name	targeted mutation 1, Frank Gonzalez
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	FXR/BAR -; FXR^-; Fxr^tm1Gonz; FXRalpha^-
Gene Symbol and Name	Nr1h4, nuclear receptor subfamily 1, group H, member 4
Gene Synonym(s)
Strain of Origin	129X1/SvJ
Chromosome	10
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.
Mutations Made By	Frank Gonzalez, National Institutes of Health (NIH/NCI)

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

hepatocellular carcinoma

Research Areas By Phenotype

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

Metabolism Research
- Lipid Metabolism
Internal/Organ Research
- Liver Defects

Genotype: Nr1h4^tm1Gonz related

Metabolism Research
- Lipid Metabolism

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - normal plasma levels of testosterone

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129X1/SvJ

homeostasis/metabolism phenotype

increased bile salt level
- serum bile acids are greatly elevated in these mice
- the increases in the bile acid pool consist of increases in cholate and its derivates including taurocholic acid and taurodeoxycholic acid
- total bile acid pool collected from liver, gallbladder and small intestine is almost 2.5-fold higher than in controls

increased circulating cholesterol level
- total cholesterol levels in serum are about double that found in wild-type mice

increased circulating triglyceride level
- serum triglyceride levels are significantly higher than in control mice

liver/biliary system phenotype

abnormal bile composition
- 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

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
STOCK Nr1h4/J

homeostasis/metabolism phenotype

increased circulating alanine transaminase level

increased circulating aspartate transaminase level

increased circulating cholesterol level

increased circulating triglyceride level

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129X1/SvJ * C57BL/6

cellular phenotype

focal hepatic necrosis

increased hepatocyte apoptosis
- TUNEL staining indicates increased hepatocyte apoptosis as mutants age

neoplasm

increased hepatocellular carcinoma incidence
- tumors are typical hepatocellular adenoma and carcinoma

increased liver adenoma incidence
- tumors are typical hepatocellular adenoma and carcinoma

increased liver tumor incidence
- both males and females develop liver tumors at 15 months of age of varying severity
- mutants fed a diet containing 2% cholestyramine, a bile acid-sequestering resin, for 3 months starting at 11 months of age when they do not have tumors, have a significantly reduced number and size of liver malignant lesions when they are older

growth/size/body region phenotype

enlarged liver
- enlarged liver is not completely due to tumor formation because hepatomegaly is seen before tumors are observed

homeostasis/metabolism phenotype

increased bile salt level
- serum and liver bile acid levels are higher in aging mutants than in wild-type controls

increased circulating aspartate transaminase level
- levels of alanine aminotransferase (ALT) are much higher in aging mutants than in controls, indicating increased liver damage

immune system phenotype

liver inflammation

liver/biliary system phenotype

abnormal liver morphology
- liver damage includes many vaculoles due to lipid deposits, vaculation due to cell damage, inflammation, and focal necrosis
- significant amounts of BrdU+ cells are detected around the damaged regions of the liver suggesting initiation of a compensatory regenerative proliferation
- starting at 9 months of age, some mutants display preneoplasms in the liver, with small foci becoming obvious at 12 months of age

enlarged liver
- enlarged liver is not completely due to tumor formation because hepatomegaly is seen before tumors are observed

focal hepatic necrosis

increased hepatocellular carcinoma incidence
- tumors are typical hepatocellular adenoma and carcinoma

increased hepatocyte apoptosis
- TUNEL staining indicates increased hepatocyte apoptosis as mutants age

increased liver adenoma incidence
- tumors are typical hepatocellular adenoma and carcinoma

increased liver tumor incidence
- both males and females develop liver tumors at 15 months of age of varying severity
- mutants fed a diet containing 2% cholestyramine, a bile acid-sequestering resin, for 3 months starting at 11 months of age when they do not have tumors, have a significantly reduced number and size of liver malignant lesions when they are older

liver inflammation

The following phenotype relates to a compound genotype created using this strain

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129X1/SvJ * C57BL/6N

cellular phenotype

increased hepatocyte apoptosis
- mutants exhibit an increase in hepatocyte apoptosis as indicated by an increase in TUNEL staining; 3 month old mutants show a higher level of apoptosis than 12 month old mutants

increased hepatocyte proliferation
- BrdU labeling indicates increased hepatocyte proliferation at 3 months of age compared to wild-type mice; at 12 months of age, proliferation has decreased but is still significantly higher than in controls

liver/biliary system phenotype

abnormal liver morphology
- mutants on a 1% cholic acid diet exhibit liver lesions indicative of severe hepatotoxicity, with numerous vacuolated and necrotic cells

enlarged liver
- liver size, as a percentage of body weight, is higher than in wild-type mice at 12 months of age

hepatic steatosis
- mutants on a regular diet or a 1% cholesterol diet exhibit more lipid containing vacuoles in the liver than wild-type

increased hepatocellular carcinoma incidence
- 6% of mutants at 12 months of age develop hepatocellular carcinoma

increased hepatocyte apoptosis
- mutants exhibit an increase in hepatocyte apoptosis as indicated by an increase in TUNEL staining; 3 month old mutants show a higher level of apoptosis than 12 month old mutants

increased hepatocyte proliferation
- BrdU labeling indicates increased hepatocyte proliferation at 3 months of age compared to wild-type mice; at 12 months of age, proliferation has decreased but is still significantly higher than in controls

increased liver adenoma incidence
- 36% of mutants at 12 months of age develop hepatocellular adenomas

increased liver cholesterol level
- mutants on a 1% cholesterol diet show 1.4-fold greater hepatic cholesterol levels

increased liver triglyceride level
- mutants on a 1% cholesterol diet show 2.4-fold greater hepatic triglyceride levels
- mutants on a regular diet show 2.2-fold greater hepatic triglyceride levels

increased liver tumor incidence
- 38% total tumor incidence in 12 month old mutants; older mice were not analyzed for further tumor incidence
- 64% of mutants at 12 months of age display preneoplastic foci
- 9% of mutants at 12 months of age develop mixed tumors consisting of hepatocellular carcinoma and hepatocholangiocellular carcinoma; mixed tumor involves a fibrous stroma and immune cell infiltrate, ductile formation and fibrosis
- both male and female mutants have liver lesions at 12 months of age; degenerative lesions consist of hypertrophic and eosinophilic hepatocytes accompanied by proliferating oval cells and lipid disposition

growth/size/body region phenotype

cachexia
- mutants on a 1% cholic acid diet exhibit severe wasting

decreased body weight
- body weight is about 20% less than in wild-type mice, regardless of age

decreased susceptibility to weight gain
- 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

enlarged liver
- liver size, as a percentage of body weight, is higher than in wild-type mice at 12 months of age

mortality/aging

increased sensitivity to induced morbidity/mortality
- about 30% of mutants die by day 7 when placed on a 1% cholic acid diet

neoplasm

increased hepatocellular carcinoma incidence
- 6% of mutants at 12 months of age develop hepatocellular carcinoma

increased liver adenoma incidence
- 36% of mutants at 12 months of age develop hepatocellular adenomas

increased liver tumor incidence
- 38% total tumor incidence in 12 month old mutants; older mice were not analyzed for further tumor incidence
- 64% of mutants at 12 months of age display preneoplastic foci
- 9% of mutants at 12 months of age develop mixed tumors consisting of hepatocellular carcinoma and hepatocholangiocellular carcinoma; mixed tumor involves a fibrous stroma and immune cell infiltrate, ductile formation and fibrosis
- both male and female mutants have liver lesions at 12 months of age; degenerative lesions consist of hypertrophic and eosinophilic hepatocytes accompanied by proliferating oval cells and lipid disposition

homeostasis/metabolism phenotype

abnormal bile salt homeostasis
- mutants on a 1% cholic acid diet exhibit higher (7-fold) urinary bile acid excretion rates than wild-type on the same diet
- 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

abnormal bile salt level
- mutants on a 1% cholic acid diet exhibit an 23-fold increase in total serum bile acid concentration
- mutants on a regular diet exhibit an 8-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
- mutants on a 1% cholic acid diet exhibit hypothermia

increased bile salt level
- 3-fold and 5.6-fold increase in serum bile acid levels in young and older mutants, respectively, compared to wild-type mice
- hepatic bile acid levels are 2x as high as in wild-type mice at 12 months of age

increased circulating cholesterol level
- mutants on a regular diet or on a 1% cholesterol diet exhibit increased serum total cholesterol levels

increased circulating phospholipid level
- mutants on a regular diet or on a 1% cholesterol diet exhibit increased phospholipid levels

increased circulating triglyceride level
- mutants on a regular or a 1% cholesterol diet exhibit increased triglyceride levels

increased liver cholesterol level
- mutants on a 1% cholesterol diet show 1.4-fold greater hepatic cholesterol levels

increased liver triglyceride level
- mutants on a 1% cholesterol diet show 2.4-fold greater hepatic triglyceride levels
- mutants on a regular diet show 2.2-fold greater hepatic triglyceride levels

References

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):731-44PubMed: 11030617 MGI: J:64792

Additional - Nr1h4^tm1Gonz related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Nr1h4
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

When maintaining a live colony, these mice can be bred as homozygotes.
- Additional Breeding and Husbandry Support
Mating System
- Homozygote x Homozygote
Citation
When using the FXR/BAR- mouse strain in a publication, please cite the originating article(s) and include JAX stock #007214 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX11 (Maximum)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous for Nr1h4<tm1Gonz>

Related Products and Services

Frozen Mouse Embryo	B6.129X1(FVB)-Nr1h4<tm1Gonz>/J Frozen Embryo	$2595.00
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Frozen Mouse Embryo	B6.129X1(FVB)-Nr1h4<tm1Gonz>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6.129X1(FVB)-Nr1h4<tm1Gonz>/J Frozen Embryo	$3373.50

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:FXR/BAR-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Nr1h4tm1Gonz

Allele Symbol: Nr1h4tm1Gonz

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

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

Genotype: Nr1h4tm1Gonz related

Mammalian Phenotype Terms by Genotype

Genotype: Nr1h4tm1Gonz/Nr1h4tm1Gonzinvolves: 129

mammalian phenotype

Genotype: Nr1h4tm1Gonz/Nr1h4tm1Gonzinvolves: 129X1/SvJ

homeostasis/metabolism phenotype

liver/biliary system phenotype

Genotype: Nr1h4tm1Gonz/Nr1h4tm1GonzSTOCK Nr1h4/J

homeostasis/metabolism phenotype

Genotype: Nr1h4tm1Gonz/Nr1h4tm1Gonzinvolves: 129X1/SvJ * C57BL/6

cellular phenotype

neoplasm

growth/size/body region phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

Genotype: Nr1h4tm1Gonz/Nr1h4tm1Gonzinvolves: 129X1/SvJ * C57BL/6N

cellular phenotype

liver/biliary system phenotype

growth/size/body region phenotype

mortality/aging

neoplasm

homeostasis/metabolism phenotype

References

Additional - Nr1h4tm1Gonz related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Nr1h4^tm1Gonz

Allele Symbol: Nr1h4^tm1Gonz

Genotype: Nr1h4^tm1Gonz related

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129X1/SvJ

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
STOCK Nr1h4/J

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129X1/SvJ * C57BL/6

Genotype: Nr1h4^tm1Gonz/Nr1h4^tm1Gonz
involves: 129X1/SvJ * C57BL/6N

Additional - Nr1h4^tm1Gonz related