An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis

摘要

The sterol regulatory element binding protein ( SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis(1,2). 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(3-5). 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(6,7). 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.