Our results have implicated the SRC-2 coactivator as a newly discovered, essential cog in the AMPK mediated energy regeneration wheel. We have elucidated a pathway that links cellular energy depletion with the act of priming the entry of dietary fuel into the body (), thereby linking the cellular energy state with the whole-animal energy state. We have shown that the cellular energy depletion sensing kinase AMPK activates the transcriptional coactivator SRC-2 which in turn transactivates the BSEP gene by synergizing with the nuclear receptor FXR, resulting in hepatic BA secretion and downstream dietary fat absorption. Interfering with this process by genetic deletion of SRC-2, in a whole-body as well as liver-specific manner, results in abrogation of hepatic BA secretion and results in fat malabsorption in the gut. These effects can be fully rescued by correcting the gut BA deficiency as well as by correcting the hepatic BSEP deficiency genetically.
Schematic depicting the cascade that links cellular energy depletion with whole-body energy repletion.
Our results suggest that AMPK promotes absorption of dietary fat in order to provide fuel for its core cellular function of fatty-acid oxidation and ATP regeneration (Minokoshi et al., 2002
). The cycle appears to begin with a low cellular ATP state, presumably due to a moderate drop in energy stores between meals, which activates AMPK and SRC-2, thereby allowing the liver to secrete BA into the gall bladder, optimally priming the gut for triglyceride absorption from the next meal, which in turn serves as a fuel for cellular fatty-acid oxidation, thus causing ATP synthesis and deactivation of the above cascade. There is some precedent for ATP levels displaying circadian oscillation (Womac et al., 2009
), presumably set by periodic food intake, while AMPK is well known to be under circadian control (Lamia et al., 2009
). By that token, we hypothesize that the cascade we have described is activated and deactivated in a circadian manner and is set by the circadian oscillation in ATP levels and AMPK activation. SRC-2 demonstrates exquisite specificity in the modulation of this pathway compared with its family members SRC-1 and SRC-3, much like we have shown in the past for glucose homeostasis (Chopra et al., 2008
Since SRC-2 has been shown to oppose energy loss (Picard et al., 2002
) and our current results have implicated it in energy uptake, it appears to function much like AMPK (Carling, 2004
; Hardie and Carling, 1997
; Kahn et al., 2005
) in preventing energy depletion. Due to its holistic nature in control of energy homeostasis, the AMPK-SRC-2 axis may serve as a potential target to fine tune whole-body energy levels, and combat obesity and associated comorbidities.