TY - JOUR
T1 - A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans
AU - Walker, Amy K.
AU - Jacobs, René L.
AU - Watts, Jennifer L.
AU - Rottiers, Veerle
AU - Jiang, Karen
AU - Finnegan, Deirdre M.
AU - Shioda, Toshi
AU - Hansen, Malene
AU - Yang, Fajun
AU - Niebergall, Lorissa J.
AU - Vance, Dennis E.
AU - Tzoneva, Monika
AU - Hart, Anne C.
AU - Näär, Anders M.
N1 - Funding Information:
We thank T. Keith Blackwell for advice on examining ER stress in C. elegans as well as members of the Näär lab and Drs. Nick Dyson, Johnathan Whetstine, Andrew Gladden, and Tom Rapoport for helpful discussions. We express our gratitude to Drs. Stefan Taubert and Raul Mostoslavsky for critical reading of the manuscript. We thank Dr. Michael Brown for the SRD13A, SCAP-deficient cells and Dr. Joachim Seemann for advice on S1P staining. We thank the Caenorhabditis Genetics Center for strains. Funding for A.K.W. was provided by the Claflin Distinguished Scholar Award and R01DK084352. Funding for A.M.N. was provided by The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School and the following grants from NIH: R01DK078332 and R01GM071449. Funding for J.L.W. was provided by NIH grant R01DK074114. Funding for research in the D.E.V. and R.L.J. labs was from the Canadian Institutes of Health Research (MOP 5182 and 4487).
PY - 2011/11/11
Y1 - 2011/11/11
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2011.09.045
DO - 10.1016/j.cell.2011.09.045
M3 - Article
C2 - 22035958
AN - SCOPUS:81055140116
SN - 0092-8674
VL - 147
SP - 840
EP - 852
JO - Cell
JF - Cell
IS - 4
ER -
