TY - JOUR
T1 - Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption
AU - Chopra, Atul R.
AU - Kommagani, Ramakrishna
AU - Saha, Pradip
AU - Louet, Jean Francois
AU - Salazar, Christina
AU - Song, Junghun
AU - Jeong, Jaewook
AU - Finegold, Milton
AU - Viollet, Benoit
AU - Demayo, Franco
AU - Chan, Lawrence
AU - Moore, David D.
AU - O'Malley, Bert W.
N1 - Funding Information:
We would like to thank S. McGuire, S. Settle, V. Yechoor, M. Tsai, A. Beaudet, A. Antebi, and H. Taegtmeyer for helpful discussion; R. Lanz for quantitative PCR setup and analysis; J. Xu for SRC-1, SRC-2, and SRC-3 null mice; the Texas Medical Center Digestive Disease Center Molecular Morphology Core (DK 56338) for help with histopathology; and L. Hagey for performing bile acid composition analysis. The BSEP promoter reporter construct was kindly provided by P. Edwards. The BSEP adenovirus was a kind gift from Y. Wakabayashi. The AMPKα DKO livers were generously provided by B.V. D.D.M. is supported by the NIH (R01 DK068804). F.D. is supported by the NIDDK (PO1 DK59820). L.C. is supported by the NIH (HL51586). B.W.O. is supported by the NIDDK (PO1 DK59820), NURSA (U19 DK062434), and a grant from the Welch Foundation.
PY - 2011/1/5
Y1 - 2011/1/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78650911273&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2010.12.001
DO - 10.1016/j.cmet.2010.12.001
M3 - Article
C2 - 21195347
AN - SCOPUS:78650911273
SN - 1550-4131
VL - 13
SP - 35
EP - 43
JO - Cell metabolism
JF - Cell metabolism
IS - 1
ER -