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CC BY V4.0, Open Access
Journal article
A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans
Cell (Cambridge), Vol.147(4), pp.840-852
2011
Handle:
https://hdl.handle.net/2376/111016
PMCID: PMC3384509
PMID: 22035958
Abstract
Sterol regulatory element-binding proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids and are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can 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 genes in the one-carbon cycle, which produces the methyl donor
S-adenosylmethionine (SAMe). Methylation is critical for the 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 feedback mechanism whereby 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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► SREBP-1 transcription factors regulate the one-carbon cycle in metazoans ► Low levels of SAMe and phosphatidylcholine (PC) activate SREBP-1 and lipogenesis ► Low PC production causes Golgi to ER relocalization of SREBP-activating proteases ► PC depletion preferentially affects SREBP-1, whereas cholesterol regulates SREBP-2
A membrane component, phosphatidylcholine, modulates lipid homeostasis via SREBP-1, suggesting a link between fatty liver disease and dietary intake of phosphatidylcholine precursors such as folates, methionine, and choline.
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Details
- Title
- A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans
- Creators
- Amy K Walker - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USARené L Jacobs - Department of Agricultural, Food and Nutritional Science, 1-32D Ag/For Centre, University of Alberta, Edmonton T6G 2M7, Alberta, CanadaJennifer L Watts - School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USAVeerle Rottiers - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USAKaren Jiang - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USADeirdre M Finnegan - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USAToshi Shioda - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USAMalene Hansen - The Sanford-Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USAFajun Yang - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USALorissa J Niebergall - Department of Biochemistry, University of Alberta, Edmonton T6G 2M7, Alberta, CanadaDennis E Vance - Department of Biochemistry, University of Alberta, Edmonton T6G 2M7, Alberta, CanadaMonika Tzoneva - School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USAAnne C Hart - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USAAnders M Näär - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USA
- Publication Details
- Cell (Cambridge), Vol.147(4), pp.840-852
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- Elsevier Inc
- Number of pages
- 5
- Grant note
- W. M. Keck Foundation; W.M. Keck Foundation
- Identifiers
- 99900547151501842
- Language
- English
- Resource Type
- Journal article