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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    • "Loss of SRC-2 −/− also affects the hepatic glucose release due to decreased expression of glucose-6-phosphatase (G6Pase) simulating the phenotypes observed in genetic disorder Von Gierke's disease (Chopra, et al. 2008). SRC-2 also stimulates absorption of fatty acids from the gut by activating the expression of bile salt export pump (BSEP) by coactivating FXR (farnesoid X receptor) under conditions of reduced energy status, thereby coordinating whole-body energy homeostasis (Chopra, et al. 2011). Even in tumor cells, SRC-2 was found to modulate fatty acid biosynthesis by distinct reprogramming of metabolic functions (Dasgupta, et al. 2012a). "
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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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    • "was described previously (Bunger et al., 2000; Chopra et al., 2011; Gehin et al., 2002 "
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