SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Open accessAbstract
Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element-binding proteins (SREBPs).SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1-4).In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles.The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice.These studies form the subject of this review.
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Srebp-1c is transcribed at extremely high levels in response to insulin.
“By contrast, Srebp-1c is transcribed at extremely high levels in response to insulin (6, 28)”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [6]
The sections “Transcriptional regulation of SREBP genes” and “SREBP-1c and the insulin/glucagon ratio” say that insulin regulates SREBP-1c transcription and increases its mRNA in rat hepatocytes. They do not establish that it is transcribed at “extremely high levels”; no page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe intracellular cholesterol economy is largely regulated by the sterol response element binding proteins (SREBPs), transcription factors that regulate genes involved in biosynthesis of cholesterol and fatty acids.
“The intracellular cholesterol economy is largely regulated by the sterol response element binding protein (SREBPs), a group of transcription factors that regulate genes involved in the biosynthesis of cholesterol and fatty acids (13).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [13]
SREBP2 primarily regulates cholesterol synthesis through increasing HMG-CoA reductase (HMGCR) expression.
“SREBP1a and SREBP1c are responsible for fatty acid metabolism and SREBP2 primarily for cholesterol synthesis through increasing the expression of HMG-CoA reductase (HMGCR) [32].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [32]
SREBPs not only activate cholesterol synthesis but also fatty acid and phospholipid synthesis.
“However, SREBPs not only activate cholesterol synthesis but also fatty acid and phospholipid synthesis (2).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [2]
Genes involved in cholesterol synthesis are coordinately up-regulated by the action of SREBP transcription factors.
“Genes involved in its synthesis are coordinately up-regulated by the action of SREBP transcription factors (2).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [2]
SREBP-1c regulates the transcription of genes involved in fatty acid metabolism, such as FASN.
“SREBP-1c regulates the transcription of genes involved in fatty acid metabolism, such as fatty acid synthase (FASN) (5–7).”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [6]
SREBP-2 regulates the transcription of cholesterol-related genes, such as HMGCR and LDLr.
“SREBP-2 regulates the transcription of cholesterol-related genes, such as 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), which catalyzes a rate-limiting step in cholesterol biosynthesis, and the low-density lipoprotein receptor (LDLr), which imports cholesterol from the blood (5–7).”
From miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011) · cites this paper as [6]
The cellular signal driving increased hepatic de novo lipogenesis can most likely be attributed to hyperinsulinemia promoting increased expression of sterol regulatory element binding protein-1c in the liver, which coordinately regulates transcription of all key enzymes involved in lipogenesis.
“The cellular signal driving this increased hepatic de novo lipogenesis can most likely be attributed to hyperinsulinemia promoting increased expression of the sterol regulatory element binding protein-1c in the liver, which coordinately regulates transcription of all of the key enzymes involved in lipogenesis (24).”
From The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome (2007) · cites this paper as [24]
XBP1 and ChREBP have been identified as inducers of hepatic lipogenesis in response to ingested CHOs (e.g., fructose and glucose) independent of insulin.
“Recently, 2 additional transcription factors, X-box binding protein 1 (XBP1) and CHO response element-binding protein (ChREBP), have been identified as inducers of hepatic lipogenesis in response to ingested CHOs (eg, fructose and glucose) that is independent of insulin.431,432”
From Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association (2011) · cites this paper as [431]
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- Authors
- Horton, J. D., Goldstein, J. L., & Brown, M. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Horton, Jay D.
- Venue
- Journal of Clinical Investigation
- Published
- 2002-05-01
- Volume
- 109
- Issue
- 9
- Pages
- 1125-1131
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4252021281
- Cited by
- 4,092
- References
- 47
- Citations by year
- 2026: 149 · 2025: 178 · 2024: 191 · 2023: 215 · 2022: 211 · 2021: 210 · 2020: 263 · 2019: 217 · 2018: 212 · 2017: 206 · 2016: 199 · 2015: 180 · 2014: 184 · 2013: 180 · 2012: 142
- FWCI
- 104.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- W. M. Keck Foundation
- American Heart Association
- National Institutes of Health (HL20948)
- 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, cholesterol biosynthesis, fatty acid synthesis, lipid homeostasis, liver, transcription factors, NADPH, triglyceride synthesis, phospholipid synthesis, bile micelles, knockout mice
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