AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity (Nature, 2009, 458:1056-1060)

報告日期: 2009/12/01
報告時間: 17:05/17:55
報告學生: 施耀翔
講評老師: 蔣輯武
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/981201-3.pdf

AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

Nature ,April 23( 2009) , vol.458, 1056–1060

Carles Canto, Zachary Gerhart-Hines, Jerome N. Feige, Marie Lagouge, Lilia Noriega, Jill C. Milne, Peter J. Elliott, Pere Puigserver & Johan Auwerx

 

Speaker: Yao-Shan Shih

Advisor: Dr. Chi-Wu Chiang

Date: 2009/12/01

Room: 602 教室

 

Abstract:

AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. AMPK is a critical regulator of mitochondrial biogenesis in response to energy deprivation. Although the mechanisms by which AMPK modulates mitochondrial gene expression are not entirely elucidated, they seem to require the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), either by increasing its expression or direct phosphorylation. It is known that PGC-1α is also activated by SIRT1- mediated deacetylation, and SIRT1 deacetylase activity is driven by NAD+ levels. The authors speculated that AMPK alters PGC-1α activity by changing its acetylation status, and whether AMPK indirectly activates SIRT1 by altering the intracellular NAD+/NADH ratio. Here the authors demonstrate that deacetylation of PGC-1α is a key mechanism by which AMPK triggers PGC-1α activity in cultured myotubes and in skeletal muscle. The authors also show that SIRT1 is a key mediator of AMPK action on PGC-1α transcriptional activity, the expression of mitochondrial and lipid metabolism genes, and O2 consumption. The acute actions of AMPK on lipid oxidation alter the balance between cellular NAD+ and NADH, which acts as a messenger to activate SIRT1. This study constitutes a step forward in the understanding of the mechanisms by which AMPK transcriptionally regulates energy expenditure. The implication of SIRT1 in the transcriptional actions of AMPK provides a possible explanation for the overlapping metabolic effects of SIRT1 and AMPK activators.

 

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