A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans

Amy K. Walker, René L. Jacobs, Jennifer L. Watts, Veerle Rottiers, Karen Jiang, Deirdre M. Finnegan, Toshi Shioda, Malene Hansen, Fajun Yang, Lorissa J. Niebergall, Dennis E. Vance, Monika Tzoneva, Anne C. Hart, Anders M. Näär

Research output: Contribution to journalArticle

196 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)840-852
Number of pages13
JournalCell
Volume147
Issue number4
DOIs
StatePublished - Nov 11 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans'. Together they form a unique fingerprint.

  • Cite this

    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. (2011). A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell, 147(4), 840-852. https://doi.org/10.1016/j.cell.2011.09.045