title: Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Atul R
authors.initials: AR
authors.lastname: Chopra
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kommagani
authors.forename: Pradip
authors.initials: P
authors.lastname: Saha
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Louet
authors.forename: Christina
authors.initials: C
authors.lastname: Salazar
authors.forename: Junghun
authors.initials: J
authors.lastname: Song
authors.forename: Jaewook
authors.initials: J
authors.lastname: Jeong
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Franco
authors.initials: F
authors.lastname: DeMayo
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D055011:Ablation Techniques; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D004041:Dietary Fats / Q000378:metabolism*; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008286:Malabsorption Syndromes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051958:Nuclear Receptor Coactivator 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001647:Bile Acids and Salts; D004041:Dietary Fats; C496283:Fxr1h protein, mouse; D051958:Nuclear Receptor Coactivator 2; D016601:RNA-Binding Proteins; D055372:AMP-Activated Protein Kinases