A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans.
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.
Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, MA 02129, USA. amy_walker@mac.com
Amy K
AK
Walker
René L
RL
Jacobs
Jennifer L
JL
Watts
Veerle
V
Rottiers
Karen
K
Jiang
Deirdre M
DM
Finnegan
Toshi
T
Shioda
Malene
M
Hansen
Fajun
F
Yang
Lorissa J
LJ
Niebergall
Dennis E
DE
Vance
Monika
M
Tzoneva
Anne C
AC
Hart
Anders M
AM
Näär
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis; D051379:Mice; D023421:Models, Animal; D010713:Phosphatidylcholines / Q000096:biosynthesis; D034622:RNA Interference; D012436:S-Adenosylmethionine / Q000096:biosynthesis; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D010713:Phosphatidylcholines; C513283:SBP-1 protein, C elegans; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D012436:S-Adenosylmethionine