Cellular Energy Depletion Resets Whole-Body Energy by Promoting Coactivator-Mediated Dietary Fuel Absorption

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Cell metabolism (Impact Factor: 17.57). 01/2011; 13(1):35-43. DOI: 10.1016/j.cmet.2010.12.001
Source: PubMed


All organisms have devised strategies to counteract energy depletion and promote fitness for survival. We show here that cellular energy depletion puts into play a surprising strategy that leads to absorption of exogenous fuel for energy repletion. The energy-depletion-sensing kinase AMPK binds, phosphorylates, and activates the transcriptional coactivator SRC-2, which in a liver-specific manner promotes absorption of dietary fat from the gut. Hepatocyte-specific deletion of SRC-2 results in intestinal fat malabsorption and attenuated entry of fat into the blood stream. This defect can be attributed to AMPK- and SRC-2-mediated transcriptional regulation of hepatic bile acid (BA) secretion into the gut, as it can be completely rescued by replenishing intestinal BA or by genetically restoring the levels of hepatic bile salt export pump (BSEP). Our results position the hepatic AMPK-SRC-2 axis as an energy rheostat, which upon cellular energy depletion resets whole-body energy by promoting absorption of dietary fuel.

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Available from: Ramakrishna Kommagani, Mar 12, 2014
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    • "Accordingly, perturbation (or more specifically, an unscheduled increase) in the cellular levels of one or more members of this coregulator family is known to be a causal factor in the genesis and/or progression of a remarkable array of clinicopathophysiologic processes [3], [4], [9], [22]. Notwithstanding the significant contributions that conventional mouse genetics have made toward our current understanding of the role of SRC family members in normal tissue function and disease progression [8], [27], [57], [58], the majority of these engineered mice fail to model the SRC overexpression phenotype that frequently drives many pathophysiologic states. This insufficiency is further exacerbated by the inability to develop cell lines that stably overexpress SRC family members, thereby denying investigators even a simple in vitro model with which to study the effects of SRC overexpression at the cellular level. "
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    ABSTRACT: As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.
    PLoS ONE 06/2014; 9(6):e98664. DOI:10.1371/journal.pone.0098664 · 3.23 Impact Factor
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    • "was described previously (Bunger et al., 2000; Chopra et al., 2011; Gehin et al., 2002 "
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    ABSTRACT: Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circadian clock.
    Cell Reports 02/2014; 6(4). DOI:10.1016/j.celrep.2014.01.027 · 8.36 Impact Factor
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    • "Based on these previously published roles for SRC-2 in controlling enzymes of fatty acid and glucose metabolism in other metabolic tissues [28], [29], [30], [31], its recurrent down regulation in human heart failure [1], and the large transcriptional component involved in the cardiac stress response, we investigated a role for SRC-2 in controlling gene expression in the heart. These investigations including genome-wide analysis, targeted expression analyses, and functional studies before and during pressure-overload induced cardiac stress reveal a novel role for SRC-2 in the regulation of cardiac transcription. "
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    ABSTRACT: A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We postulated that SRC-2 suppression plays a mechanistic role in the stress response and that SRC-2 activity is an important regulator of the adult heart gene expression profile. Genome-wide microarray analysis, confirmed with targeted gene expression analyses revealed that genetic ablation of SRC-2 activates the "fetal gene program" in adult mice as manifested by shifts in expression of a) metabolic and b) sarcomeric genes, as well as associated modulating transcription factors. While these gene expression changes were not accompanied by changes in left ventricular weight or cardiac function, imposition of transverse aortic constriction (TAC) predisposed SRC-2 knockout (KO) mice to stress-induced cardiac dysfunction. In addition, SRC-2 KO mice lacked the normal ventricular hypertrophic response as indicated through heart weight, left ventricular wall thickness, and blunted molecular signaling known to activate hypertrophy. Our results indicate that SRC-2 is involved in maintenance of the steady-state adult heart transcriptional profile, with its ablation inducing transcriptional changes that mimic a stressed heart. These results further suggest that SRC-2 deletion interferes with the timing and integration needed to respond efficiently to stress through disruption of metabolic and sarcomeric gene expression and hypertrophic signaling, the three key stress responsive pathways.
    PLoS ONE 12/2012; 7(12):e53395. DOI:10.1371/journal.pone.0053395 · 3.23 Impact Factor
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