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A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans
Open accessAbstract
Summary Sterol Regulatory Element-Binding Proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids, and therefore are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can result in excess stored fat and contribute to obesity, fatty liver disease and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls production of the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a mechanism where maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.
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Metadata
- Authors
- Walker, A. K., Jacobs, R. L., Watts, J. L., Rottiers, V., Jiang, K., Finnegan, D. M., Shioda, T., Hansen, M., Yang, F., Niebergall, L. J., Vance, D. E., Tzoneva, M., Hart, A. C., & Näär, A. M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 147
- Issue
- 4
- Pages
- 840-852
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2130844401
- Cited by
- 465
- References
- 58
- FWCI
- 9.42
- Type
- journal article
- Language
- en
- Open access
- bronze
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