Overview

These Nr1h3 knock-out mice lose their ability to respond normally to dietary cholesterol. This strain may be useful in studies involving fertility, innate immunity, metabolism, and the effects of dietary cholesterol, lipids and carbohydrates

Donating Investigator

David Mangelsdorf, UT Southwestern Medical Center

Genetic overview

Genetic Background	Generation

Nr1h3^tm1Djm

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Nr1h3	nuclear receptor subfamily 1, group H, member 3

View Genetics

Research Applications

Reproductive Biology Research
Metabolism Research
Internal/Organ Research
Immunology, Inflammation and Autoimmunity Research
Cardiovascular Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

View Price List

Details

Detailed Description

Homozygous Nr1h3 (nuclear receptor subfamily 1, group H, member 3) targeted mutation mice lose their ability to respond normally to dietary cholesterol. Mice maintained on cholesterol diets fail to induce transcription of the Cyp7a1 (cytochrome P450, family 7, subfamily a, polypeptide 1) gene, a rate-limiting enzyme in bile acid synthesis, and fail to induce expression of ABCG5 (ATP-binding cassette, sub-family G (WHITE), member 5) and ABCG8 (ATP-binding cassette, sub-family G (WHITE), member 8), ATP-binding cassette transporters that are required for cholesterol secretion into bile. Large amounts of cholesterol rapidly accumulate in the liver leading to impaired hepatic function. Impaired reverse cholesterol transport from peripheral tissues is also observed. The ability to regulate lipids and carbohydrates is also lost. Defects in innate immune responses by activated macrophages have also been described. Males are not infertile, but show a significantly higher number of testicular apoptotic cells than wildtype mice. Testosterone production is significantly lower. It is not known whether genetic background affects the phenotype associated with this mutation.

Development

Exons 3-6, containing the complete DNA-binding domain and majority of the ligand-binding domain, were replaced with a neomycin resistance cassette. The mutation was created in SM1 embryonic stem (ES) cells derived from 129S6/SvEvTac mice. This strain was backcrossed to a 129-derived strain of unknown subline for seven generations by the donating laboratory.

Control Suggestions

002448 129S1/SvImJ

Additional Information

Considerations for Choosing Controls

Selected References

Peet DJ; Turley SD; Ma W; Janowski BA; Lobaccaro JM; Hammer RE; Mangelsdorf DJ. 1998. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93(5):693-704PubMed: 9630215 MGI: J:47971

View All References

Genetics

Nr1h3^tm1Djm

Allele Symbol: Nr1h3^tm1Djm

Allele Name	targeted mutation 1, David J Mangelsdorf
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	LXRalpha (-); Nr1h3^-
Gene Symbol and Name	Nr1h3, nuclear receptor subfamily 1, group H, member 3
Gene Synonym(s)
Strain of Origin	129S6/SvEvTac
Chromosome	2
Molecular Note	Exons 3-6 encoding the DNA-binding and ligand-binding domains (amino acids 87-327) were replaced with a neomycin resistance gene via homologous recombination. Northern blot and Western blot analysis of liver from homozygous mutant animals verified the absence of mRNA and protein expression.
Mutations Made By	David Mangelsdorf, UT Southwestern Medical Center

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).

ovarian hyperstimulation syndrome

Research Areas By Phenotype

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

Reproductive Biology Research
- Fertility Defects
Metabolism Research
- Lipid Metabolism
Internal/Organ Research
- Liver Defects
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
  - Macrophage defects
Cardiovascular Research
- Hypercholesterolemia

Mammalian Phenotype Terms by Genotype

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

Genotype: Nr1h3^tm1Djm/Nr1h3^tm1Djm
involves: 129S6/SvEvTac * C57BL/6

cardiovascular system phenotype

increased vascular permeability
- in the ovaries of superovulated-mice compared to in similarly treated wild-type

ovary hemorrhage
- superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

growth/size/body region phenotype

enlarged ovary
- following superovulation protocols, ovary size is increased compared with ovaries from similarly treated wild-type mice
- Normal - however, estradiol-treated mice have normal sized ovaries

increased liver weight
- 3 months on a high cholesterol diet leads to a doubling in liver mass without increasing body weight

homeostasis/metabolism phenotype

abnormal bile salt homeostasis
- less fecal excretion of bile acid occurs in mice fed the high cholesterol diet compared to control mice
- mice fail to increase their pool of bile acid in response to a high cholesterol diet as wild-type mice do
- the ratio of cholic acid to muricholic acid within the bile acid pool is significantly higher than controls on a chow-fed diet, and does not decrease when fed a high cholesterol diet

decreased circulating luteinizing hormone level
- plasma LH levels are almost half that of controls

decreased circulating testosterone level
- testosterone production in the testes is significantly reduced compared to controls

increased circulating alanine transaminase level
- serum alanine transaminase levels are increased in mice that are fed a high cholesterol diet

increased circulating aspartate transaminase level
- serum aspartate transaminase levels are increased in mice that are fed a high cholesterol diet

increased circulating cholesterol level
- there is a 15- to 20- fold increase in liver cholesterol levels 7 days after being switched to a high (2%) cholesterol diet while only a modest increase is observed in control mice
- when fed an intermediate (0.2%) cholesterol diet, mice have increases of 3- and 10- fold after 7 and 22 days on the diet

increased circulating estradiol level
- superovulated-mice compared to in similarly treated wild-type

increased circulating LDL cholesterol level
- serum LDL levels are increased 5-fold in mice that are fed a high cholesterol diet

increased erythrocyte sedimentation rate
- following superovulation protocols, mice exhibit an increase in blood sediment rate compared with wild-type mice indicating inflammation

increased liver cholesterol level
- both total and free when fed Western diet
- there is a 15- to 20- fold increase in liver cholesterol levels 7 days after being switched to a high (2%) cholesterol diet while only a modest increase is observed in control mice
- when fed an intermediate (0.2%) cholesterol diet, mice have increases of 3- and 10- fold after 7 and 22 days on the diet

immune system phenotype

increased inflammatory response
- following superovulation protocols, mice exhibit an increase in blood sediment rate compared with wild-type mice indicating inflammation

increased susceptibility to bacterial infection
- bacterial burden in the liver of day 2 of infection is 2 logs higher than controls
- mice succumb to infection of Listeria monocytogenes 2-3 days earlier than controls

cellular phenotype

abnormal male germ cell apoptosis
- apoptosis of germ cells within seminiferous tubules is more than double that of controls

liver/biliary system phenotype

hepatic steatosis
- on high (2%) cholesterol diets, livers develop fatty deposits that increase in number and size with time while control mice exhibit no abnormalities
- the liver appears pale and is double in size, inflammatory foci are developing, and signs of liver degeneration are evident after 3 months on the diet

increased liver cholesterol level
- both total and free when fed Western diet
- there is a 15- to 20- fold increase in liver cholesterol levels 7 days after being switched to a high (2%) cholesterol diet while only a modest increase is observed in control mice
- when fed an intermediate (0.2%) cholesterol diet, mice have increases of 3- and 10- fold after 7 and 22 days on the diet

increased liver weight
- 3 months on a high cholesterol diet leads to a doubling in liver mass without increasing body weight

liver degeneration
- hepatocytes have lost most of their normal cell structure after 90 days on a high cholesterol diet
- increased serum levels of alanine and aspartate amino transferases are also indicitave of liver injury
- signs of liver degeneration are evident after 3 months on a high cholesterol diet

pale liver
- liver appears white after 3 months on a high cholesterol diet due to presence of cholesterol filled droplets

endocrine/exocrine gland phenotype

abnormal corpus luteum morphology
- superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

abnormal ovary physiology
- following follicle retrieval, a greater number of follicles are expulsed with 45% dead oocytes or empty zonae pellucidae unlike in similarly treated wild-type mice

enlarged ovary
- following superovulation protocols, ovary size is increased compared with ovaries from similarly treated wild-type mice
- Normal - however, estradiol-treated mice have normal sized ovaries

ovary cysts
- superovulated-mice exhibit hemorrhagic cysts unlike similarly treated wild-type mice

ovary hemorrhage
- superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - circulating cholesterol level both total and free
- Normal - circulating free fatty acid level
- Normal - circulating triglyceride level
- Normal - liver free fatty acid level
- Normal - liver triglyceride level
- Normal - when fed Western diet

mortality/aging

increased sensitivity to induced morbidity/mortality
- mice succumb to infection of Listeria monocytogenes 2-3 days earlier than controls

reproductive system phenotype

abnormal corpus luteum morphology
- superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

abnormal male germ cell apoptosis
- apoptosis of germ cells within seminiferous tubules is more than double that of controls

abnormal ovary physiology
- following follicle retrieval, a greater number of follicles are expulsed with 45% dead oocytes or empty zonae pellucidae unlike in similarly treated wild-type mice

abnormal superovulation
- ompared with similarly treated wild-type mice
- superovulated-mice exhibit increased follicle expulsion, increased number of dead oocytes or empty zona pellucida, enlarged ovaries, ovarian cysts, rare ovarian hemorrhage, increased ovarian vascular permeability, circulating estradiol, and inflammation compared with similarly treated wild-type mice

enlarged ovary
- following superovulation protocols, ovary size is increased compared with ovaries from similarly treated wild-type mice
- Normal - however, estradiol-treated mice have normal sized ovaries

ovary cysts
- superovulated-mice exhibit hemorrhagic cysts unlike similarly treated wild-type mice

ovary hemorrhage
- superovulated-mice rarely exhibit hemorrhage of the corpus luteum unlike similarly treated wild-type mice

References

Peet DJ; Turley SD; Ma W; Janowski BA; Lobaccaro JM; Hammer RE; Mangelsdorf DJ. 1998. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93(5):693-704PubMed: 9630215 MGI: J:47971

Additional - Nr1h3^tm1Djm related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Nr1h3
- Genotyping resources and troubleshooting
Breeding Considerations

When maintained as a live colony, homozygotes or heterozygotes may be bred. The donating laboratory reports that breeders between the ages of 2 and 6 months of age show best productivity. They also recommend Teklad Global diets which are free of soybeans for experimental purposes. Soybeans are suspected of masking adrenal and neurodegenerative phenotypes associated with compound mutant strains that incorporate this Nr1h3 mutation (please review published literature). Our "Diet Information" link provides further details of the maintenance feed used at The Jackson Laboratory.
- Additional Breeding and Husbandry Support
Citation
When using the 129-Nr1h3^tm1Djm/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #013762 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous for Nr1h3<tm1Djm>

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

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.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

JAX® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCT(S)" means biological materials supplied by JACKSON, and their derivatives. "SERVICES" means projects conducted by JACKSON for other parties that may include but are not limited to the use of MICE or PRODUCTS. "RECIPIENT" means each recipient of MICE, PRODUCTS, or SERVICES provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE, PRODUCTS or SERVICES from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON’s prior written authorization.

No Warranty

MICE, PRODUCTS AND SERVICES ARE PROVIDED "AS IS". JACKSON EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS, IMPLIED, OR STATUTORY, WITH RESPECT TO MICE, PRODUCTS OR SERVICES, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY WARRANTY OF NON-INFRINGEMENT OF ANY PATENT, TRADEMARK, OR OTHER INTELLECTUAL PROPERTY RIGHTS.

Credit for PRODUCTS or SERVICES

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of, PRODUCTS or SERVICES, JACKSON will, at its option, provide credit or replacement for the PRODUCT received or the SERVICES provided; JACKSON makes no other representations and this shall be the exclusive remedy of the purchaser. Please note specific policy for live mice.

Animal Care and Use for SERVICES

Consistent with the requirement for a written understanding regarding animal care and use, the JACKSON Animal Care and Use Committee will review the animal care and use protocol(s) associated with any SERVICES to be performed at JACKSON, and JACKSON shall have ultimate responsibility and authority for the care of animals while on site or in JACKSON custody.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS, or SERVICES, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS, or SERVICES from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE, PRODUCTS or SERVICES are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or SERVICES. In addition, special terms and conditions of sale of certain MICE, PRODUCTS, or SERVICES may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and SERVICES by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or SERVICES shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or SERVICES by JACKSON.

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Nr1h3tm1Djm

Allele Symbol: Nr1h3tm1Djm

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:

Mammalian Phenotype Terms by Genotype

Genotype: Nr1h3tm1Djm/Nr1h3tm1Djminvolves: 129S6/SvEvTac * C57BL/6

cardiovascular system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

immune system phenotype

cellular phenotype

liver/biliary system phenotype

endocrine/exocrine gland phenotype

mammalian phenotype

mortality/aging

reproductive system phenotype

References

Additional - Nr1h3tm1Djm related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Nr1h3^tm1Djm

Allele Symbol: Nr1h3^tm1Djm

Genotype: Nr1h3^tm1Djm/Nr1h3^tm1Djm
involves: 129S6/SvEvTac * C57BL/6

Additional - Nr1h3^tm1Djm related