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2 results on '"Chopra AR"'

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

Author

Chopra AR, Kommagani R, Saha P, Louet JF, Salazar C, Song J, Jeong J, Finegold M, Viollet B, DeMayo F, Chan L, Moore DD, and O'Malley BW

Subjects
ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters biosynthesis, ATP-Binding Cassette Transporters genetics, Ablation Techniques, Animals, Bile Acids and Salts metabolism, Cells, Cultured, 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 genetics, Phosphorylation, Promoter Regions, Genetic, RNA-Binding Proteins metabolism, Transcriptional Activation, AMP-Activated Protein Kinases metabolism, ATP-Binding Cassette Transporters metabolism, Dietary Fats metabolism, Nuclear Receptor Coactivator 2 deficiency, Nuclear Receptor Coactivator 2 metabolism
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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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2. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.

Author

Chopra AR, Louet JF, Saha P, An J, Demayo F, Xu J, York B, Karpen S, Finegold M, Moore D, Chan L, Newgard CB, and O'Malley BW

Subjects
Animals, Cells, Cultured, Fasting, Female, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Glucose-6-Phosphatase metabolism, Glycogen Storage Disease Type I metabolism, Hepatocytes metabolism, Kidney metabolism, Liver Glycogen metabolism, Male, Mice, Mice, Knockout, Nuclear Receptor Coactivator 2 genetics, RNA Interference, Receptors, Retinoic Acid metabolism, Response Elements, Retinoic Acid Receptor alpha, Transcription, Genetic, Triglycerides metabolism, Glucose metabolism, Glucose-6-Phosphatase genetics, Glycogen Storage Disease Type I genetics, Liver metabolism, Nuclear Receptor Coactivator 2 metabolism
Abstract

Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the plasma. Mutations in G6Pase result in Von Gierke's disease (glycogen storage disease-1a), a potentially fatal genetic disorder. We have identified the transcriptional coactivator SRC-2 as a regulator of fasting hepatic glucose release, a function that SRC-2 performs by controlling the expression of hepatic G6Pase. SRC-2 modulates G6Pase expression directly by acting as a coactivator with the orphan nuclear receptor RORalpha. In addition, SRC-2 ablation, in both a whole-body and liver-specific manner, resulted in a Von Gierke's disease phenotype in mice. Our results position SRC-2 as a critical regulator of mammalian glucose production.

Published
2008
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