Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption

Cell Metab. 2011 Jan 5;13(1):35-43. doi: 10.1016/j.cmet.2010.12.001.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Ablation Techniques
  • Animals
  • Bile Acids and Salts / metabolism
  • Cells, Cultured
  • Dietary Fats / metabolism*
  • Energy Metabolism
  • Gene Expression Regulation
  • Hep G2 Cells
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Intestinal Absorption
  • Liver / cytology
  • Liver / enzymology
  • Liver / metabolism
  • Malabsorption Syndromes / metabolism
  • Malabsorption Syndromes / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Coactivator 2 / deficiency*
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA-Binding Proteins / metabolism
  • Transcriptional Activation

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, mouse
  • Bile Acids and Salts
  • Dietary Fats
  • Fxr1h protein, mouse
  • Nuclear Receptor Coactivator 2
  • RNA-Binding Proteins
  • AMP-Activated Protein Kinases