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Updated: Jul 13, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene
J Yang1, J L Goldstein, R E Hammer
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
Abstract:
Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcription-stimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. S1P is a potential target for lipid-lowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70-90% of S1P alleles in liver were inactivated, and S1P mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75%. Low density lipoprotein (LDL) receptor mRNA declined by 50%, as did the clearance of (125)I-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that S1P inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.
Insights
Site-1 protease (S1P) inhibition significantly reduces cholesterol and fatty acid synthesis in mice. Complete S1P blockade is likely necessary for effective lipid-lowering drug development.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Site-1 protease (S1P) processes sterol regulatory element-binding proteins (SREBPs) to regulate lipid synthesis.
- S1P is a potential therapeutic target for managing lipid disorders.
- The in vivo effects of S1P inhibition were previously unknown.
Purpose of the Study:
- To investigate the physiological consequences of S1P gene disruption in mice.
- To assess the potential of S1P as a target for lipid-lowering therapies.
Main Methods:
- Generation of mice with germ-line S1P gene disruption (embryonic lethal).
- Development of an inducible liver-specific S1P knockout mouse model using a floxed S1P allele and Cre-lox system.
- Administration of interferon (IFN) to induce Cre recombinase activity and S1P gene inactivation in the liver.
Main Results:
- Inducible S1P disruption in the liver led to significant reductions in S1P mRNA and protein levels.
- Nuclear SREBP levels and expression of SREBP target genes decreased substantially.
- Hepatocyte cholesterol and fatty acid biosynthesis were reduced by 75%.
- Low-density lipoprotein (LDL) receptor mRNA decreased by 50%, impacting LDL clearance and plasma cholesterol levels.
Conclusions:
- S1P plays a critical role in regulating lipid biosynthesis in vivo.
- S1P inhibitors show promise as lipid-lowering agents.
- Near-complete inhibition of S1P activity may be required for therapeutic efficacy.
