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SIRT1 regulates adaptive response of the growth hormone--insulin-like growth factor-I axis under fasting conditions in liver.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Sep 10; Vol. 110 (37), pp. 14948-53. Date of Electronic Publication: 2013 Aug 26. - Publication Year :
- 2013
-
Abstract
- Adaptation under fasting conditions is critical for survival in animals. Sirtuin 1 (SIRT1), a protein deacetylase, plays an essential role in adaptive metabolic and endocrine responses under fasting conditions by modifying the acetylation status of various proteins. Fasting induces growth hormone (GH) resistance in the liver, leading to decreased serum insulin-like growth factor-I (IGF-I) levels as an endocrine adaptation for malnutrition; however, the underlying mechanisms of this action remain to be fully elucidated. Here we report that in vivo knockdown of SIRT1 in the liver restored the fasting-induced decrease in serum IGF-I levels and enhanced the GH-dependent increase in IGF-I levels, indicating that SIRT1 negatively regulates GH-dependent IGF-I production in the liver. In vitro analysis using hepatocytes demonstrated that SIRT1 suppresses GH-dependent IGF-I expression, accompanied by decreased tyrosine phosphorylation on signal transducer and activator of transcription (STAT) 5. GST pull-down assays revealed that SIRT1 interacts directly with STAT5. When the lysine residues adjacent to the SH2 domain of STAT5 were mutated, STAT5 acetylation decreased concomitant with a decrease in its transcriptional activity. Knockdown of SIRT1 enhanced the acetylation and GH-induced tyrosine phosphorylation of STAT5, as well as the GH-induced interaction of the GH receptor with STAT5. These data indicate that SIRT1 negatively regulates GH-induced STAT5 phosphorylation and IGF-I production via deacetylation of STAT5 in the liver. In addition, our findings explain the underlying mechanisms of GH resistance under fasting conditions, which is a known element of endocrine adaptation during fasting.
- Subjects :
- Acetylation
Adaptation, Physiological
Animals
Cells, Cultured
Gene Knockdown Techniques
Hep G2 Cells
Hepatocytes drug effects
Hepatocytes metabolism
Humans
Insulin-Like Growth Factor I genetics
Male
Mice
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Niacinamide pharmacology
Phosphorylation
RNA, Messenger genetics
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Receptors, Somatotropin genetics
Receptors, Somatotropin metabolism
STAT5 Transcription Factor chemistry
STAT5 Transcription Factor genetics
STAT5 Transcription Factor metabolism
Sirtuin 1 antagonists & inhibitors
Sirtuin 1 genetics
src Homology Domains
Fasting metabolism
Growth Hormone metabolism
Insulin-Like Growth Factor I metabolism
Liver metabolism
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23980167
- Full Text :
- https://doi.org/10.1073/pnas.1220606110