Journal article
An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis
Nature (London), Vol.442(7103), pp.700-704
08/10/2006
Handle:
https://hdl.handle.net/2376/108721
PMID: 16799563
Abstract
The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis. We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms. Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes. We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15, including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.
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Details
- Title
- An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis
- Creators
- Fajun Yang - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown, Massachusetts 02129, USABryan W VoughtJohn S SatterleeAmy K WalkerZ-Y Jim SunJennifer L WattsRosalie DeBeaumontR Mako SaitoSven G HybertsShaosong YangChristine MacolLakshmanan IyerRobert TjianSander van den HeuvelAnne C HartGerhard WagnerAnders M Näär
- Publication Details
- Nature (London), Vol.442(7103), pp.700-704
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- England
- Grant note
- R01 CA127990 / NCI NIH HHS R01 DK074114-01 / NIDDK NIH HHS R01 DK074114 / NIDDK NIH HHS
- Identifiers
- 99900547014001842
- Language
- English
- Resource Type
- Journal article