SIRT4 Regulates Fatty Acid Oxidation and Mitochondrial Gene Expression in Liver and Muscle Cells

被引:244
|
作者
Nasrin, Nargis [1 ]
Wu, Xiaoping [1 ]
Fortier, Eric [1 ]
Feng, Yajun [1 ]
Bare, Olivia Claire [1 ]
Chen, Sumiao [1 ]
Ren, Xianglin [1 ]
Wu, Zhidan [1 ]
Streeper, Ryan S. [1 ]
Bordone, Laura [1 ]
机构
[1] Novartis Inst BioMed Res Inc, Cardiovasc & Metab Dis Area, Cambridge, MA 02139 USA
关键词
GLUTAMATE-DEHYDROGENASE; AMINO-GROUPS; SIRTUINS; METABOLISM; GLUCOSE; RESTRICTION; PGC-1-ALPHA; ACETYLATION; INSIGHTS; NAD;
D O I
10.1074/jbc.M110.124164
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
SIRT4, a member of the sirtuin family, has been implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase. However, the role of this enzyme in the regulation of metabolism in other tissues is unknown. In this study we investigated whether depletion of SIRT4 would enhance liver and muscle metabolic functions. To do this SIRT4 was knocked down using an adenoviral shRNA in mouse primary hepatocytes and myotubes. We observed a significant increase in gene expression of mitochondrial and fatty acid metabolism enzymes in hepatocytes with reduced SIRT4 levels. SIRT4 knockdown also increased SIRT1 mRNA and protein levels both in vitro and in vivo. In agreement with the increased fatty acid oxidation (FAO) gene expression, we showed a significant increase in FAO in SIRT4 knockdown primary hepatocytes compared with control, and this effect was dependent on SIRT1. In primary myotubes, knockdown of SIRT4 resulted in increased FAO, cellular respiration, and pAMPK levels. When SIRT4 was knocked down in vivo by tail vein injection of a shRNA adenovirus, we observed a significant increase in hepatic mitochondrial and FAO gene expression consistent with the findings in primary hepatocytes. Taken together these findings demonstrate that SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes.
引用
收藏
页码:31995 / 32002
页数:8
相关论文
共 50 条
  • [21] INHIBITION OF MITOCHONDRIAL FATTY-ACID OXIDATION IN PENTENOIC ACID-INDUCED FATTY LIVER
    THAYER, WS
    FEDERATION PROCEEDINGS, 1983, 42 (07) : 1854 - 1854
  • [22] Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver
    Schirmer, Helena
    Brandao Pereira, Talita Carneiro
    Rico, Eduardo Pacheco
    Rosemberg, Denis Broock
    Bonan, Carla Denise
    Bogo, Mauricio Reis
    Souto, Andre Arigony
    MOLECULAR BIOLOGY REPORTS, 2012, 39 (03) : 3281 - 3289
  • [23] Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4,PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver
    Helena Schirmer
    Talita Carneiro Brandão Pereira
    Eduardo Pacheco Rico
    Denis Broock Rosemberg
    Carla Denise Bonan
    Maurício Reis Bogo
    André Arigony Souto
    Molecular Biology Reports, 2012, 39 : 3281 - 3289
  • [24] Pioglitazone alters the expression of genes involved in fatty acid oxidation and mitochondrial function in human skeletal muscle
    Coletta, Dawn K.
    Wajcberg, Estela
    Sriwi-Jitkamol, Apiradee
    Jenkinson, Christopher P.
    Musi, Nicolas
    Cersosimo, Eugenio
    Defronzo, Ralph A.
    DIABETES, 2007, 56 : A62 - A63
  • [25] SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy (vol 9, pg 2163, 2017)
    Lang, Alexander
    Anand, Ruchika
    Altinoluk-Hambuechen, Simone
    Ezzahoini, Hakima
    Stefanski, Anja
    Iram, Afshin
    Bergmann, Laura
    Urbach, Jennifer
    Boehler, Philip
    Haensel, Jan
    Franke, Manuel
    Stuehler, Kai
    Krutmann, Jean
    Scheller, Juergen
    Stork, Bjoern
    Reichert, Andreas S.
    Piekorz, Roland P.
    AGING-US, 2018, 10 (09): : 2536 - 2536
  • [26] Effect of Fatty Acids on Insulin Response, Mitochondrial Function, and Gene Expression in Skeletal Muscle Cells
    Hirabara, Sandro M.
    Lambertucci, Rafael H.
    Nachbar, Renato T.
    Camargo, Luiz F. T.
    Silveira, Leonardo R.
    Maechler, Pierre
    Curi, Rui
    JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS, 2009, 2 (4-5) : 209 - 209
  • [27] SIRT4 Protects Müller Glial Cells Against Apoptosis by Mediating Mitochondrial Dynamics and Oxidative Stress
    Luo, Hongdou
    Jin, Ming
    Hu, Haijian
    Ying, Qian
    Hu, Piaopiao
    Sheng, Weiwei
    Huang, Yi
    Xu, Ke
    Lu, Chuming
    Zhang, Xu
    MOLECULAR NEUROBIOLOGY, 2024,
  • [28] MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4
    Lang, Alexander
    Grether-Beck, Susanne
    Singh, Madhurendra
    Kuck, Fabian
    Jakob, Sascha
    Kefalas, Andreas
    Altinoluk-Hambuchen, Simone
    Graffmann, Nina
    Schneider, Maren
    Lindecke, Antje
    Brenden, Heidi
    Felsner, Ingo
    Ezzahoini, Hakima
    Marini, Alessandra
    Weinhold, Sandra
    Vierkotter, Andrea
    Tigges, Julia
    Schmidt, Stephan
    Stuhler, Kai
    Kohrer, Karl
    Uhrberg, Markus
    Haendeler, Judith
    Krutmann, Jean
    Piekorz, Roland P.
    AGING-US, 2016, 8 (03): : 484 - 509
  • [29] Acute fatty liver of pregnancy and mitochondrial fatty acid oxidation. Consequences for the offspring
    Anon, B.
    Barbet, C.
    Gendrot, C.
    Labarthe, F.
    Bacq, Y.
    ARCHIVES DE PEDIATRIE, 2017, 24 (08): : 777 - 782
  • [30] Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis
    Yan, Seungyeon
    Moon, Subin
    Hur, Soojung Claire
    Jeong, Seung Min
    BMB REPORTS, 2023, 56 (12) : 651 - 656