Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice
Open accessAbstract
The synthesis of cholesterol and fatty acids (FA) in the liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here, we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in the liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for the maximal SREBP-1c expression and high rates of FA synthesis.
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Genes in the cholesterol-biosynthesis pathway, including TFs such as SREBP that regulate lipid synthesis, are all upregulated in LOAD-risk-allele iMGs.
“The de novo cholesterol and fatty acid synthesis in LOAD-risk-allele iMGs may contribute to LD accumulation: genes in the cholesterol-biosynthesis pathway, including TFs (such as SREBP) that regulate lipids synthesis35, were all upregulated (Fig. 4b and Supplementary Fig. 8).”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [35]
De novo cholesterol and fatty acid synthesis in LOAD-risk-allele iMGs may contribute to LD accumulation.
“The de novo cholesterol and fatty acid synthesis in LOAD-risk-allele iMGs may contribute to LD accumulation: genes in the cholesterol-biosynthesis pathway, including TFs (such as SREBP) that regulate lipids synthesis35, were all upregulated (Fig. 4b and Supplementary Fig. 8).”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [35]
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References 34 · Cited by 134
Research works printed but not linked: 30
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- Authors
- Rong, S., Cortés, V. A., Rashid, S., Anderson, N. N., McDonald, J. G., Liang, G., Moon, Y.-A., Hammer, R. E., & Horton, J. D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
- Corresponding author
- Horton, Jay D
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-02-28
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5348127
- OpenAlex
- W2592226915
- Cited by
- 134
- References
- 34
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 17 · 2023: 10 · 2022: 13 · 2021: 11 · 2020: 17 · 2019: 10 · 2018: 9 · 2017: 13
- FWCI
- 13.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (HL-20948)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- SREBP-1c, SREBP2, liver X receptor, cholesterol biosynthesis, fatty acid synthesis, triglyceride synthesis, hepatocytes, LDL receptor, PCSK9, transcriptional regulation, hepatic lipid metabolism
- MeSH terms
- Liver X Receptors, Animals, Cholesterol, Fatty Acids, Gene Expression Regulation, Liver, Transcription, Genetic, Mice, Knockout, Mice, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Gene Knockout Techniques
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