A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans
| Autor: | René L. Jacobs, Fajun Yang, Monika Tzoneva, Deirdre M. Finnegan, Lorissa J. Niebergall, Jennifer L. Watts, Amy K. Walker, Anders M. Näär, Veerle Rottiers, Toshi Shioda, Anne C. Hart, Karen Jiang, Malene Hansen, Dennis E. Vance |
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| Rok vydání: | 2011 |
| Předmět: |
S-Adenosylmethionine
endocrine system Biology Endoplasmic Reticulum General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine RNA interference Cell Line Tumor Phosphatidylcholine Animals Humans Caenorhabditis elegans Caenorhabditis elegans Proteins Transcription factor 030304 developmental biology 0303 health sciences Cholesterol Biochemistry Genetics and Molecular Biology(all) Lipogenesis food and beverages Sterol Sterol regulatory element-binding protein Cell biology chemistry Biochemistry 030220 oncology & carcinogenesis Models Animal Phosphatidylcholines Sterol Regulatory Element Binding Protein 1 RNA Interference lipids (amino acids peptides and proteins) Transcription Factors |
| Zdroj: | Cell. 147(4):840-852 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2011.09.045 |
| Popis: | SummarySterol 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. |
| Databáze: | OpenAIRE |
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