The Scap/SREBP Pathway Is Essential for Developing Diabetic Fatty Liver and Carbohydrate-Induced Hypertriglyceridemia in Animals
Open accessAbstract
Insulin resistance leads to hypertriglyceridemia and hepatic steatosis and is associated with increased SREBP-1c, a transcription factor that activates fatty acid synthesis. Here, we show that steatosis in insulin-resistant ob/ob mice was abolished by deletion of Scap, an escort protein necessary for generating nuclear isoforms of all three SREBPs. Scap deletion reduced lipid synthesis and prevented fatty livers despite persistent obesity, hyperinsulinemia, and hyperglycemia. Scap deficiency also prevented steatosis in mice fed high-fat diets. Steatosis was also prevented when siRNAs were used to silence Scap in livers of sucrose-fed hamsters, a model of diet-induced steatosis and hypertriglyceridemia. This silencing reduced all three nuclear SREBPs, decreasing lipid biosynthesis and abolishing sucrose-induced hypertriglyceridemia. These results demonstrate that SREBP activation is essential for development of diabetic hepatic steatosis and carbohydrate-induced hypertriglyceridemia, but not insulin resistance. Inhibition of SREBP activation has therapeutic potential for treatment of hypertriglyceridemia and fatty liver disease.
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Some mouse models of obesity and non-insulin-dependent diabetes have also shown a dissociation between fatty liver and glucose tolerance.
“A similar dissociation was already reported in some murine models of obesity and non-insulin dependent diabetes mellitus [44,45].”
From Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats (2015) · cites this paper as [45]
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- Authors
- Moon, Y.-A., Liang, G., Xie, X., Frank-Kamenetsky, M., Fitzgerald, K., Koteliansky, V., Brown, M. S., Goldstein, J. L., & Horton, J. D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Horton, Jay D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 15
- Issue
- 2
- Pages
- 240-246
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3662050
- OpenAlex
- W2007809519
- Cited by
- 320
- References
- 29
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 23 · 2023: 19 · 2022: 25 · 2021: 19 · 2020: 23 · 2019: 21 · 2018: 31 · 2017: 25 · 2016: 26 · 2015: 27 · 2014: 18 · 2013: 26 · 2012: 10
- FWCI
- 19.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Foundation for the National Institutes of Health
- Alnylam Pharmaceuticals
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK081182, PL1DK081182)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- SCAP, SREBP, SREBP-1c, hepatic steatosis, hypertriglyceridemia, insulin resistance, ob/ob mice, high-fat diet, sucrose feeding, hepatic lipid synthesis, fatty acid synthesis
- MeSH terms
- Animals, Fatty Liver, Cricetinae, Heme, Lipids, Membrane Proteins, Mice, Transgenic, Immunoblotting, Hypertriglyceridemia, DNA Primers, Gene Silencing, RNA Interference, Intracellular Signaling Peptides and Proteins, Mice, Sterol Regulatory Element Binding Protein 1, Real-Time Polymerase Chain Reaction
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