Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis

被引:59
作者
Brahma, Manoja K. [1 ]
Adam, Rene C. [1 ]
Pollak, Nina M. [1 ]
Jaeger, Doris [1 ]
Zierler, Kathrin A. [1 ]
Poecher, Nadja [1 ]
Schreiber, Renate [1 ]
Romauch, Matthias [1 ]
Moustafa, Tarek [1 ]
Eder, Sandra [1 ]
Ruelicke, Thomas [2 ,3 ]
Preiss-Landl, Karina [1 ]
Lass, Achim [1 ]
Zechner, Rudolf [1 ]
Haemmerle, Guenter [1 ]
机构
[1] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria
[2] Biomodels Austria, A-1210 Vienna, Austria
[3] Univ Vet Med, Inst Lab Anim Sci, A-1210 Vienna, Austria
基金
奥地利科学基金会;
关键词
adipose triglyceride lipase; cardiac lipid and energy metabolism; ER stress; ENDOPLASMIC-RETICULUM STRESS; ADIPOSE TRIGLYCERIDE LIPASE; PPAR-ALPHA; METABOLIC REGULATOR; BETA-KLOTHO; ENERGY-METABOLISM; FGF21; MICE; LIPOLYSIS; TISSUE;
D O I
10.1194/jlr.M044784
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
Fibroblast growth factor 21 (FGF21) is a PPAR alpha-regulated gene elucidated in the liver of PPAR alpha-deficient mice or PPAR alpha agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPAR alpha-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism.jlr Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis.
引用
收藏
页码:2229 / 2241
页数:13
相关论文
共 47 条
[1]  
Badman MK, 2007, CELL METAB, V5, P426, DOI 10.1016/j.cmet.2007.05.002
[2]   Fibroblast Growth Factor 21 Controls Glycemia via Regulation of Hepatic Glucose Flux and Insulin Sensitivity [J].
Berglund, Eric D. ;
Li, Candice Y. ;
Bina, Holly A. ;
Lynes, Sara E. ;
Michael, M. Dodson ;
Shanafelt, Armen B. ;
Kharitonenkov, Alexei ;
Wasserman, David H. .
ENDOCRINOLOGY, 2009, 150 (09) :4084-4093
[3]  
Crooks D. R., 2014, HUM MOL GENET
[4]   Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart [J].
Dogan, Sukru Anil ;
Pujol, Claire ;
Maiti, Priyanka ;
Kukat, Alexandra ;
Wang, Shuaiyu ;
Hermans, Steffen ;
Senft, Katharina ;
Wibom, Rolf ;
Rugarli, Elena I. ;
Trifunovic, Aleksandra .
CELL METABOLISM, 2014, 19 (03) :458-469
[5]   Fibroblast Growth Factor 21: A Novel Metabolic Regulator With Potential Therapeutic Properties in Obesity/Type 2 Diabetes Mellitus [J].
Dostalova, I. ;
Haluzikova, D. ;
Haluzik, M. .
PHYSIOLOGICAL RESEARCH, 2009, 58 (01) :1-7
[6]   Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo [J].
Fisher, Ffolliott M. ;
Estall, Jennifer L. ;
Adams, Andrew C. ;
Antonellis, Patrick J. ;
Bina, Holly A. ;
Flier, Jeffrey S. ;
Kharitonenkov, Alexei ;
Spiegelman, Bruce M. ;
Maratos-Flier, Eleftheria .
ENDOCRINOLOGY, 2011, 152 (08) :2996-3004
[7]  
FOLCH J, 1957, J BIOL CHEM, V226, P497
[8]   Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice [J].
Fuchs, Claudia D. ;
Claudel, Thierry ;
Kumari, Pooja ;
Haemmerle, Guenter ;
Pollheimer, Marion J. ;
Stojakovic, Tatjana ;
Scharnagl, Hubert ;
Halilbasic, Emina ;
Gumhold, Judith ;
Silbert, Dagmar ;
Koefeler, Harald ;
Trauner, Michael .
HEPATOLOGY, 2012, 56 (01) :270-280
[9]   The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man [J].
Gaelman, Cecilia ;
Lundasen, Tomas ;
Kharitonenkov, Alexei ;
Bina, Holly A. ;
Eriksson, Mats ;
Hafstroem, Ingiaeld ;
Dahlin, Maria ;
Amark, Per ;
Angelin, Bo ;
Rudling, Mats .
CELL METABOLISM, 2008, 8 (02) :169-174
[10]   Coping with Endoplasmic Reticulum Stress in the Cardiovascular System [J].
Groenendyk, Jody ;
Agellon, Luis B. ;
Michalak, Marek .
ANNUAL REVIEW OF PHYSIOLOGY, VOL 75, 2013, 75 :49-67