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Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene
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.
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In plasma, total cholesterol and triglycerides are lower in all mice with the exception that triglycerides are largely unchanged in Spring LKO.
“In plasma, (iii) total cholesterol and triglycerides are lower in all mice with the only exception being that the latter is largely unchanged in Spring LKO.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
Ablation of Scap, Mbtps1, and Spring results in decreased cholesterol synthesis in isolated primary hepatocytes.
“Moreover, (iv) ablation of all 3 genes results in decreased cholesterol synthesis in isolated primary hepatocytes”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
In the liver, cholesterol levels are lower in Scap and Spring mice, but unchanged in Mbtps1 mice.
“In the liver (i) cholesterol levels are lower in Scap and Spring mice, but unchanged in Mbtps1 mice”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
Global ablation of Spring and Mbtps1 in mice is embryonically lethal.
“Additionally, while global ablation of Spring and Mbtps1 in mice is embryonically lethal10,21”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
Constitutive deletion of Mbtps1, Scap, or Spring leads to in utero lethality.
“Similarly, constitutive deletion of either Mbtps121, Scap31, or Spring10 leads to in utero lethality.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
Ablation of Scap, Mbtps1, and Spring uniformly reduced the expression of Srebf1 and Srebf2 target genes.
“and (v) uniformly reduced the expression of Srebf1 and Srebf2 target genes”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
In the liver, triglyceride levels are lower in Scap, Mbtps1, and Spring mice.
“and (ii) triglyceride levels are lower in all three”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [21]
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SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
Self-citationER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P
Kim, J. Y., Garcia-Carbonell, R., Yamachika, S., Zhao, P., Dhar, D., Loomba, R., Kaufman, R. J., Saltiel, A. R., & Karin, M. (2018) · Cell · doi:10.1016/j.cell.2018.08.020 · Cited by 333
Moon, Y.-A., Liang, G., Xie, X., Frank-Kamenetsky, M., Fitzgerald, K., Koteliansky, V., Brown, M. S., Goldstein, J. L., & Horton, J. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.017 · Cited by 320
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Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187
Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77
Chao, L. C., Wroblewski, K., Zhang, Z., Pei, L., Vergnes, L., Ilkayeva, O. R., Ding, S. Y., Reue, K., Watt, M. J., Newgard, C. B., et al. (2009) · Diabetes · doi:10.2337/db09-0763 · Cited by 154
“Primer sequences are listed in supplementary Table 2 and as previously described (16,17,48).”
Bock, H. H., Jossin, Y., May, P., Bergner, O., & Herz, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401770200 · Cited by 102
Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans
Hendrix, S., Kingma, J., Ottenhoff, R., Valiloo, M., Svecla, M., Zijlstra, L. F., Sachdev, V., Kovac, K., Levels, J. H. M., Jongejan, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40943-1 · Cited by 34
MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3
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SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P
Hendrix, S., Tan, J. M. E., Ndoj, K., Kingma, J., Valiloo, M., Zijlstra, L. F., Ottenhoff, R., Seidah, N. G., Loregger, A., Kober, D. L., et al. (2024) · Molecular and Cellular Biology · doi:10.1080/10985549.2024.2348711 · Cited by 9
Metadata
- Authors
- Yang, J., Goldstein, J. L., Hammer, R. E., Moon, Y.-A., Brown, M. S., & Horton, J. D.
- Affiliations
- Departments of Molecular Genetics, Biochemistry, and Internal Medicine, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-11-20
- Volume
- 98
- Issue
- 24
- Pages
- 13607-13612
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 217
- References
- 1
- Language
- en
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