Over the last decade, a number of transcription factors and coregulators have been characterized as important regulators of energy homeostasis. Despite these recent advances, relatively few molecular targets have been described that control energy balance in a holistic manner. Interestingly, our recently published data and preliminary studies now show that Steroid Receptor Coactivator-2 (SRC-2) is involved not only in energy dissipation, but also in the dietary absorption of fat. SRC-2 achieves this function through the coordinated regulation of a hepatic gene cassette, which includes the Bile Salt Export Pump (BSEP) that is necessary for bile acid secretion and reabsorption. Interfering with this process by hepatic-specific ablation of SRC-2 results in fat malabsorption in the gut, which can be rescued by dietary administration of bile acids, or by hepatic re-expression of BSEP. Furthermore, SRC-2 not only modulates the energy balance at both ends of the energy equation (accretion and dissipation), but itself is also sensitive to changes in energy status. In response to low cellular energy, we show that AMPK phosphorylates SRC-2, which increases its intrinsic transcriptional activity and drives these two metabolic regulators to target genes necessary for energy intake. Moreover, we found that SRC-2 enhances AMPK phosphorylation of histones, an event that has been reported to enhance target gene expression. Collectively, these findings form the basis of our PPG renewal for Project 1, where we hypothesize that SRC-2 functions as a master regulator of energy homeostasis in coordination with AMPK.
The precise mechanistic underpinnings ofthe AMPK/SRC-2 'energy sensor' axis are completely unexplored, as Project 1 is based upon entirely new findings. Regulation of whole body energetics has profound implications for the exploding co-morbidities of the metabolic syndrome that plague our country. As such, detailing such molecular pathways would open new intervention avenues for developing small molecule inhibitors to treat these metabolic diseases.
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