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

Abstract

Summary All organisms have devised strategies to counteract energy depletion in order to 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. We found that 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 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.

Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

“…Conversely, the double AMPKα1/α2 KO blunted Bsep expression and affected hepatic BA content (15). This contrasts with the lack of effect of liver LKB1 KO, which strongly downregulates AMPKα1 and α2 activity, yet has no effect on Bsep expression (37).…”

“…Similarly, the SIRT1 and the AMPK pathways act in concert in mouse liver, in which a simultaneous decrease or increase in AMPK and SIRT1 activities occurs in the refed or fasted state respectively (14). Thus, a link between cellular energy levels and NR coregulator activity has been established, which was more recently extended to SRC-2, whose ability to regulate the basal expression level of the FXR target gene Bsep is positively controlled by AMPK (15). Thus, although not formally tested, the possibility arises that the metabolic status of cells impinges on FXR transcriptional activity through an interaction with energy-sensitive transcriptional coregulators, which is supported by the demonstration that glucose induces the expression of FXR (16).…”

The Role of Canalicular ABC Transporters in Cholestasis

“…Activating signal cointegrator-2-containing complex recruitment by chenodeoxycholic acid increases FXR-induced transactivation, because this coactivator complex methylates the ABCB11 promoter histones (Ananthanarayanan et al, 2011). Steroid receptor coactivator-2 activation by liver kinase B1 and AMP-activated protein kinase also promotes FXR-induced transactivation by acetylation of promoter histones (Chopra et al, 2011). The liver receptor homolog-1 and the oxidative stress sensor nuclear factor erythroid 2-related factor 2 finally transactivate ABCB11 by binding to specific response elements in the ABCB11 promoter (Weerachayaphorn et al, 2009).…”

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

“…Previous findings from our laboratory identified steroid receptor coactivator 2 (SRC-2, also known as NCOA2, TIF2, and GRIP1), a potent transcriptional coregulator for nuclear receptors (NRs) and other transcription factors (13), as a critical coordinator of energy homeostasis (14)(15)(16)(17). Importantly, recent findings from Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells.…”