title: SIRT1 regulates adaptive response of the growth hormone--insulin-like growth factor-I axis under fasting conditions in liver.
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.
authors: Division of Diabetes and Endocrinology and Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Masaaki
authors: M
authors: Yamamoto
authors: Genzo
authors: G
authors: Iguchi
authors: Hidenori
authors: H
authors: Fukuoka
authors: Kentaro
authors: K
authors: Suda
authors: Hironori
authors: H
authors: Bando
authors: Michiko
authors: M
authors: Takahashi
authors: Hitoshi
authors: H
authors: Nishizawa
authors: Susumu
authors: S
authors: Seino
authors: Yutaka
authors: Y
authors: Takahashi
mesh_terms: D000107:Acetylation; D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D005215:Fasting / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D013006:Growth Hormone / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009536:Niacinamide / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D009536:Niacinamide; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
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