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

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.

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

“…To regulate SREBP‐mediated transcription, several transcriptional activators and repressors interact with SREBP proteins (Yang et al ., 2006). Using GST pull‐down assay, we observed that HDGF directly interacted with SREBP‐1a (Fig.…”

“…At the same time, these transcriptional cofactors control specific gene transcription. A mediator complex including ARC105 and CDK8 has been shown to be essential for SREBP control of cholesterol and fatty acid homeostasis (Yang et al ., 2006; Zhao et al ., 2012). In this study, we found that HDGF promoted SREBP‐1‐mediated gene transcription via blocking recruitment of CTBP1 transcription repressor in HCC cells (Fig.…”

UNC-64 and RIC-4, the plasma membrane-associated SNAREs syntaxin and SNAP-25, regulate fat storage in nematode Caenorhabditis elegans

“…Studies in mammals have indicated that some of the cellular metabolic sensors can also regulate the metabolic homeostasis and behavioral responses in the nervous system [40,41] , such as the sbp-1 signaling pathway, the mdt-15 signaling pathway, and the nhr-49 signaling pathway in C. elegans [6,7] .…”

“…As shown in Fig. 5 sbp-1 will suppress fat storage [7] , whereas mutation of nhr-49 will increase fat storage [6] . The possible role of genetic interactions of unc-64 and ric-4 with metabolic sensors and coordinated regulation of metabolic pathway in regulating fat storage was further investigated.…”

“…Down-regulating the transforming growth factor-beta (TGF-β) pathway promotes fat accumulation in adults [5] . Moreover, NHR-49, MDT-15 and SBP-1 mainly constitute the components of metabolic sensors and coordinate regulation of metabolic pathway to function in the metabolic sensing mechanisms in C. elegans [6,7] .…”