The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD+

被引:282
作者
Gerhart-Hines, Zachary [1 ,2 ,3 ]
Dominy, John E., Jr. [1 ,2 ]
Blaettler, Sharon M. [1 ,2 ]
Jedrychowski, Mark P. [2 ]
Banks, Alexander S. [1 ,2 ]
Lim, Ji-Hong [1 ,2 ]
Chim, Helen [1 ,2 ]
Gygi, Steven P. [2 ]
Puigserver, Pere [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[3] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA
基金
美国国家卫生研究院; 瑞士国家科学基金会;
关键词
ORPHAN NUCLEAR RECEPTOR; ELEGANS LIFE-SPAN; SKELETAL-MUSCLE; GENE-EXPRESSION; TRANSCRIPTIONAL CONTROL; MITOCHONDRIAL-FUNCTION; PGC-1; COACTIVATORS; ENERGY-METABOLISM; REGULATES SIRT1; CELL-SURVIVAL;
D O I
10.1016/j.molcel.2011.12.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The NAD(+)-dependent deacetylase SIRT1 is an evolutionarily conserved metabolic sensor of the Sirtuin family that mediates homeostatic responses to certain physiological stresses such as nutrient restriction. Previous reports have implicated fluctuations in intracellular NAD(+) concentrations as the principal regulator of SIRT1 activity. However, here we have identified a cAMP-induced phosphorylation of a highly conserved serine (S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic deacetylase activity independently of changes in NAD(+) levels. Attenuation of SIRT1 expression or the use of a nonphosphorylatable SIRT1 mutant prevented cAMP-mediated stimulation of fatty acid oxidation and gene expression linked to this pathway. Overexpression of SIRT1 in mice significantly potentiated the increases in fatty acid oxidation and energy expenditure caused by either pharmacological beta-adrenergic agonism or cold exposure. These studies support a mechanism of Sirtuin enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis.
引用
收藏
页码:851 / 863
页数:13
相关论文
共 44 条
[11]   SIRT1: recent lessons from mouse models [J].
Herranz, Daniel ;
Serrano, Manuel .
NATURE REVIEWS CANCER, 2010, 10 (12) :819-823
[12]   Insights into the sirtuin mechanism from ternary complexes containing NAD+ and acetylated peptide [J].
Hoff, Kevin G. ;
Avalos, Jose L. ;
Sens, Kristin ;
Wolberger, Cynthia .
STRUCTURE, 2006, 14 (08) :1231-1240
[13]   Adopting new orphans into the family of metabolic regulators [J].
Hummasti, Sarah ;
Tontonoz, Peter .
MOLECULAR ENDOCRINOLOGY, 2008, 22 (08) :1743-1753
[14]   Estrogen-related receptor α directs peroxisome proliferator-activated receptor at signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle [J].
Huss, JM ;
Torra, IP ;
Staels, B ;
Giguère, V ;
Kelly, DP .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (20) :9079-9091
[15]   Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase [J].
Imai, S ;
Armstrong, CM ;
Kaeberlein, M ;
Guarente, L .
NATURE, 2000, 403 (6771) :795-800
[16]   Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1 [J].
Iwabu, Masato ;
Yamauchi, Toshimasa ;
Okada-Iwabu, Miki ;
Sato, Koji ;
Nakagawa, Tatsuro ;
Funata, Masaaki ;
Yamaguchi, Mamiko ;
Namiki, Shigeyuki ;
Nakayama, Ryo ;
Tabata, Mitsuhisa ;
Ogata, Hitomi ;
Kubota, Naoto ;
Takamoto, Iseki ;
Hayashi, Yukiko K. ;
Yamauchi, Naoko ;
Waki, Hironori ;
Fukayama, Masashi ;
Nishino, Ichizo ;
Tokuyama, Kumpei ;
Ueki, Kohjiro ;
Oike, Yuichi ;
Ishii, Satoshi ;
Hirose, Kenzo ;
Shimizu, Takao ;
Touhara, Kazushige ;
Kadowaki, Takashi .
NATURE, 2010, 464 (7293) :1313-1319
[17]   The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms [J].
Kaeberlein, M ;
McVey, M ;
Guarente, L .
GENES & DEVELOPMENT, 1999, 13 (19) :2570-2580
[18]   CK2 Is the Regulator of SIRT1 Substrate-Binding Affinity, Deacetylase Activity and Cellular Response to DNA-Damage [J].
Kang, Hyeog ;
Jung, Jae-Won ;
Kim, Myung K. ;
Chung, Jay H. .
PLOS ONE, 2009, 4 (08)
[19]   Orphan nuclear receptor NOR-1 enhances 3′,5′-cyclic adenosine 5′-monophosphate-dependent uncoupling protein-1 gene transcription [J].
Kumar, Naresh ;
Liu, Dianxin ;
Wang, Haibo ;
Robidoux, Jacques ;
Collins, Sheila .
MOLECULAR ENDOCRINOLOGY, 2008, 22 (05) :1057-1064
[20]   Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α [J].
Lagouge, Marie ;
Argmann, Carmen ;
Gerhart-Hines, Zachary ;
Meziane, Hamid ;
Lerin, Carles ;
Daussin, Frederic ;
Messadeq, Nadia ;
Milne, Jill ;
Lambert, Philip ;
Elliott, Peter ;
Geny, Bernard ;
Laakso, Markku ;
Puigserver, Pere ;
Auwerx, Johan .
CELL, 2006, 127 (06) :1109-1122