Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N8+2pN1 (26-FEB-06)   Donating Investigator Bob Farese,   Gladstone Inst of Cardiovascular Disease

Description
Mice that are homozygous null for this targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Southern blot analysis and RT-PCR indicated the targeted gene was disrupted. These mice lack cholesterol ester synthesis in liver and intestine and are resistant to diet-induced hypercholesterolemia and cholesterol gallstone formation. In homozygous mice fed regular diet, acyl CoA: cholesterol acyltransferase (ACAT) enzyme activity was reduced by 92% in intestine, and by 99% in liver. Homozygous mice fed high-fat/high cholesterol diet had low ACAT activity. Although ACAT2 deficient mice absorb less cholesterol than wild-type mice when fed a high fat/ high cholesterol diet, histological examination indicated enterocytes in the mutant mice were normal. This mutant mouse strain represents a model that may be useful in studies related to human resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation.

Development
A targeting vector containing approximately 1.5 kb Soat2 sequence, neomycin resistance, and herpes simplex virus thymidine kinase genes was utilized in the construction of this mutant. The Soat2 sequence targeted in the construct corresponded to the carboxy terminal and 28% of the ACAT2 protein. The construct was electroporated into 129S4/SvJae derived RF8 embryonic stem (ES) cells. Selected ES cells were then used to generate mice.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

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.

Soat2^tm1Far/Soat2^tm1Far

        involves: 129S4/SvJae * C57BL/6J

• homeostasis/metabolism phenotype
• abnormal cholesterol homeostasis (MGI Ref ID J:82032)
  • reduction in cholesterol ester synthesis in the small intestine and liver
• decreased circulating cholesterol level (MGI Ref ID J:82032)
  • homozygotes exhibit resistance to diet-induced hypercholesterolemia; cholesterol in the VLDL, LDL and IDL fractions is reduced
• decreased circulating LDL cholesterol level (MGI Ref ID J:82032)
  • homozygotes fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet exhibit reduced cholesterol in the LDL fraction compared to wild-type
• decreased circulating VLDL cholesterol level (MGI Ref ID J:82032)
  • homozygotes fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet exhibit reduced cholesterol in the VLDL fraction compared to wild-type
• increased circulating HDL cholesterol level (MGI Ref ID J:82032)
  • mutants fed a western diet (20% fat and 0.15% cholesterol) exhibit increases in plasma HDL cholesterol
• decreased cholesterol absorption (MGI Ref ID J:82032)
  • cholesterol absorption in homozygotes fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet is 85% lower than in wild-type
• increased circulating triglyceride level (MGI Ref ID J:82032)
  • homozygotes fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet or a chow diet exhibit elevated serum triglyceride level compared to wild-type fed the same diet; VLDL, IDL, and LDL fractions are increased
• liver/biliary system phenotype
• abnormal gall bladder physiology (MGI Ref ID J:82032)
  • homozygotes exhibit resistance to diet-induced cholesterol gallstone formation
• abnormal bile composition (MGI Ref ID J:82032)
  • mutants on a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet exhibit bile cholesterol concentrations that are 30% lower than in wild-type mice
• increased resistance to hepatic steatosis (MGI Ref ID J:82032)
  • when fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet, mutants do not develop fat-laden livers as seen in wild-type mice on the same diet
• digestive/alimentary phenotype
• abnormal small intestine morphology (MGI Ref ID J:82032)
  • free cholesterol levels are increased by 30% in the small intestine of mutants fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet
• decreased cholesterol absorption (MGI Ref ID J:82032)
  • cholesterol absorption in homozygotes fed a high-fat (7.5%), high-cholesterol (1.25%) and 0.5% cholic acid diet is 85% lower than in wild-type

View Research Applications

Research Applications

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

Soat2^tm1Far related

Cardiovascular Research
Hypercholesterolemia (Resistant)

Metabolism Research
Lipid Metabolism

Research Tools
Metabolism Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Soat2tm1Far
Allele Name		targeted mutation 1, Robert V Farese
Allele Type		Targeted (knock-out)
Common Name(s)		ACAT2;
Mutation Made By		Bob Farese,   Gladstone Inst of Cardiovascular Disease
Strain of Origin		129S4/SvJae
ES Cell Line Name		RF8
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Soat2, sterol O-acyltransferase 2
Chromosome		15
Gene Common Name(s)		ACACT2; ACAT2; ARGP2; Acat-2; D15Wsu97e; DNA segment, Chr 15, Wayne State University 97, expressed; MGC116732;
Molecular Note		The gene was disrupted by replacement of 1.5 kb of C-terminal sequences with a neomycin resistance cassette via homologous recombination. The gene targeting event results in deletion of 28% of the protein sequence. Absence of gene expression in homozygous mutant animals was confirmed by RT-PCR analysis of mRNA from liver and small intestines. [MGI Ref ID J:82032]

Genotyping

Genotyping Information

Genotyping Protocols

NEOTD (Generic Neo), STD PCR, vers. 1
Soat2^tm1Far, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Buhman KK; Accad M; Novak S; Choi RS; Wong JS; Hamilton RL; Turley S; Farese RV Jr. 2000. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 6(12):1341-7. [PubMed: 11100118]  [MGI Ref ID J:82032]

Additional References

Soat2^tm1Far related

Bell TA rd; Kelley K; Wilson MD; Sawyer JK; Rudel LL. 2007. Dietary fat-induced alterations in atherosclerosis are abolished by ACAT2-deficiency in ApoB100 only, LDLr-/- mice. Arterioscler Thromb Vasc Biol 27(6):1396-402. [PubMed: 17431188]  [MGI Ref ID J:134910]

Brown JM; Bell TA rd; Alger HM; Sawyer JK; Smith TL; Kelley K; Shah R; Wilson MD; Davis MA; Lee RG; Graham MJ; Crooke RM; Rudel LL. 2008. Targeted depletion of hepatic ACAT2-driven cholesterol esterification reveals a non-biliary route for fecal neutral sterol loss. J Biol Chem 283(16):10522-34. [PubMed: 18281279]  [MGI Ref ID J:136556]

Lee RG; Kelley KL; Sawyer JK; Farese RV Jr; Parks JS; Rudel LL. 2004. Plasma cholesteryl esters provided by lecithin:cholesterol acyltransferase and acyl-coenzyme a:cholesterol acyltransferase 2 have opposite atherosclerotic potential. Circ Res 95(10):998-1004. [PubMed: 15486318]  [MGI Ref ID J:103854]

Lee RG; Shah R; Sawyer JK; Hamilton RL; Parks JS; Rudel LL. 2005. ACAT2 contributes cholesteryl esters to newly secreted VLDL, whereas LCAT adds cholesteryl ester to LDL in mice. J Lipid Res 46(6):1205-12. [PubMed: 15805543]  [MGI Ref ID J:128885]

Temel RE; Lee RG; Kelley KL; Davis MA; Shah R; Sawyer JK; Wilson MD; Rudel LL. 2005. Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2. J Lipid Res 46(11):2423-31. [PubMed: 16150828]  [MGI Ref ID J:104775]

Willner EL; Tow B; Buhman KK; Wilson M; Sanan DA; Rudel LL; Farese RV Jr. 2003. Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A 100(3):1262-7. [PubMed: 12538880]  [MGI Ref ID J:81836]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	Coat color expected from breeding:Black
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
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.

General Terms and Conditions

See Terms of Use

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.

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Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

For additional Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (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 with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, 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 The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials 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 The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory 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 The Jackson Laboratory, 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 The Jackson Laboratory, 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 services by The Jackson Laboratory.