These Srebf1 knock-out mice exhibit an increase of liver cholesterol content and a reduction of plasma cholesterol and plasma triglycerides levels.
Dr. Jay D. Horton, Univ of Texas SW Med Center at Dallas
Mice that are homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. The targeted mutation results in a total ablation of the SREBP-1c transcript and only a slight redution in levels of the alternate SREBP-1a transcript. There is a 50% increase in level of SREBP-2 transcript and increases in transcripts of enzymes utilized in cholesterol biosynthesis. Liver cholesterol content is increased while plasma cholesterol and plasma triglycerides levels are reduced. There is a reduction of expression of all genes required for fatty acid and triglyceride synthesis. Administration of liver X receptor (LXR) agonist did not result in increased levels of SREBP-1a transcript or in liver triglycerides. This mutant mouse strain represents a model that may be useful in studies of transcriptional control of fatty acid and triglyceride biosynthesis.
A targeting vector containing two copies of the herpes simplex virus thymidine kinase gene, a modified bacterial lacZ gene with a nuclear localization signal and the ACN cassette was used to disrupt the first exon and a portion of the promoter for the SREBP-1c isoform. The ACN cassette, containing the neomycin resistance gene and Cre recombinase gene under the control of angiotensin-converting enzyme promoter, is flanked by loxP sites. Cre-mediated recombination during spermatogenesis removed the cassette leaving one loxP site and resulted in lacZ gene expression controlled by the endogenous SREBP-1c promoter. The construct was electroporated into 129S6/SvEv derived SM-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were backcrossed to B6;129S6 mice.
|Expressed Gene||lacZ, beta-galactosidase, E. coli|
|Site of Expression||Liver|
|Allele Name||targeted mutation 1, Michael S Brown|
|Allele Type||Targeted (Null/Knockout, Reporter)|
|Allele Synonym(s)||SREBP-1c -; SREBP-1c null|
|Gene Symbol and Name||Srebf1, sterol regulatory element binding transcription factor 1|
|Gene Synonym(s)||ADD-1; ADD1; SREBP-1; SREBP-1a; SREBP-1c; SREBP1; SREBP1a; SREBP1c; Srebp1; bHLHd1|
|Expressed Gene||lacZ, beta-galactosidase, E. coli|
|Site of Expression||Liver|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||An in-frame lacZ gene with a nuclear localization signal was inserted into exon 1c of the gene. A loxP flanked neomycin resistance and Angiotensin-cre cassette (ACN) was inserted following the lacZ gene. The neomycin/cre cassette was autocatalytically removed in the male germline by activation of the Ace promoter in testis. RNase protection assays on liver RNA from homozygous mice demonstrated that the 1c isoform transcript was not detectable, while expression of the 1a isoform was unaffected. Western blot analysis confirmed that the expression of the encoded protein was greatly reduced from this allele; in addition, beta-galactosidase expression was detected from this allele in frozen liver sections.|
|Mutations Made By|| |
Dr. Jay Horton, Univ of Texas SW Med Center at Dallas
This strain originated on a B6;129S6 background and is maintained as a homozygote.
|Please inquire about possible genotypes.|
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