1. The TSC complex is required for the benefits of dietary protein restriction on stress resistance in vivo.
- Author
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Harputlugil E, Hine C, Vargas D, Robertson L, Manning BD, and Mitchell JR
- Subjects
- Amino Acids, Essential metabolism, Animals, Cells, Cultured, Diet, Protein-Restricted, Gene Knockout Techniques, Insulin Resistance, Ischemia metabolism, Liver blood supply, Liver pathology, Mechanistic Target of Rapamycin Complex 1, Mice, 129 Strain, Mice, Inbred C57BL, Multiprotein Complexes metabolism, Protein Serine-Threonine Kinases physiology, Reperfusion Injury diet therapy, Stress, Physiological, TOR Serine-Threonine Kinases metabolism, Tuberous Sclerosis Complex 1 Protein, Liver metabolism, Reperfusion Injury metabolism, Tumor Suppressor Proteins physiology
- Abstract
Protein restriction (PR) is important for the benefits of dietary restriction on longevity and stress resistance, but relevant nutrient sensors and downstream effectors in mammals remain poorly defined. We used PR-mediated protection from hepatic ischemia reperfusion injury to probe genetic requirements for the evolutionarily conserved nutrient sensors GCN2 and mTORC1 in stress resistance. One week of PR reduced free amino acids and circulating growth factors, activating GCN2 and mTORC1 repressor tuberous sclerosis complex (TSC). However, although GCN2 was dispensable for PR-induced protection, hepatic TSC1 was required. PR improved hepatic insulin sensitivity in a TSC1-dependent manner prior to ischemia, facilitating increased prosurvival signaling and reduced apoptosis after reperfusion. These benefits were partially abrogated by pharmacological PI3K inhibition or genetic deletion of the insulin receptor in hepatocytes. In conclusion, improved insulin sensitivity upon short-term PR required TSC1, facilitated increased prosurvival signaling after injury, and contributed partially to PR-mediated resistance to clinically relevant ischemia reperfusion injury., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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