Cell, 2011-11, Vol.147 (4), p.840-852
2011
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Details
- Autor(en) / Beteiligte
- Titel
- A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans
- Ist Teil von
- Cell, 2011-11, Vol.147 (4), p.840-852
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] ► 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2011.09.045Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3384509
- Format
- –
- Schlagworte
- Animalia, Animals, Caenorhabditis elegans - metabolism, Caenorhabditis elegans Proteins - metabolism, Cell Line, Tumor, cholesterol, Endoplasmic Reticulum - metabolism, fatty liver, genes, homeostasis, Humans, insulin resistance, Lipogenesis, liver, metabolic diseases, metabolic syndrome, methylation, Mice, Models, Animal, obesity, phosphatidylcholines, Phosphatidylcholines - biosynthesis, proteins, RNA Interference, S-adenosylmethionine, S-Adenosylmethionine - biosynthesis, Sterol Regulatory Element Binding Protein 1 - metabolism, transcription (genetics), Transcription Factors - metabolism