TY - JOUR
T1 - DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity
AU - Liu, Li
AU - Shi, Xiao Jing
AU - Bharadwaj, Kalyani G.
AU - Ikeda, Shota
AU - Yamashita, Haruyo
AU - Yagyu, Hiroaki
AU - Schaffer, Jean E.
AU - Yu, Yi Hao
AU - Goldberg, Ira J.
PY - 2009/12/25
Y1 - 2009/12/25
N2 - Intracellular lipid accumulation in the heart is associated with cardiomyopathy, yet the precise role of triglyceride (TG) remains unclear. With exercise, wild type hearts develop physiologic hypertrophy. This was associated with greater TG stores and a marked induction of the TG-synthesizing enzyme diacylglycerol (DAG) acyltransferase 1 (DGAT1). Transgenic overexpression of DGAT1 in the heart using the cardiomyocytespecific a-myosin heavy chain (MHC) promoter led to approximately a doubling of DGAT activity and TG content and reductions of a35% in cardiac ceramide, 26% in DAG, and 20% in free fatty acid levels. Cardiac function assessed by echocardiography and cardiac catheterization was unaffected. These mice were then crossed with animals expressing long-chain acyl-CoA synthetase via theMHCpromoter (MHC-ACS), which develop lipotoxic cardiomyopathy. MHC-DGAT1XMHC-ACS double transgenic male mice had improved heart function; fractional shortening increased by 74%, and diastolic function improved compared with MHC-ACS mice. The improvement of heart function correlated with a reduction in cardiac DAG and ceramide and reduced cardiomyocyte apoptosis but increased fatty acid oxidation. In addition, the survival of the mice was improved. Our study indicates that TG is not likely to be a toxic lipid species directly, but rather it is a feature of physiologic hypertrophy and may serve a cytoprotective role in lipid overload states. Moreover, induction of DGAT1 could be beneficial in the setting of excess heart accumulation of toxic lipids.
AB - Intracellular lipid accumulation in the heart is associated with cardiomyopathy, yet the precise role of triglyceride (TG) remains unclear. With exercise, wild type hearts develop physiologic hypertrophy. This was associated with greater TG stores and a marked induction of the TG-synthesizing enzyme diacylglycerol (DAG) acyltransferase 1 (DGAT1). Transgenic overexpression of DGAT1 in the heart using the cardiomyocytespecific a-myosin heavy chain (MHC) promoter led to approximately a doubling of DGAT activity and TG content and reductions of a35% in cardiac ceramide, 26% in DAG, and 20% in free fatty acid levels. Cardiac function assessed by echocardiography and cardiac catheterization was unaffected. These mice were then crossed with animals expressing long-chain acyl-CoA synthetase via theMHCpromoter (MHC-ACS), which develop lipotoxic cardiomyopathy. MHC-DGAT1XMHC-ACS double transgenic male mice had improved heart function; fractional shortening increased by 74%, and diastolic function improved compared with MHC-ACS mice. The improvement of heart function correlated with a reduction in cardiac DAG and ceramide and reduced cardiomyocyte apoptosis but increased fatty acid oxidation. In addition, the survival of the mice was improved. Our study indicates that TG is not likely to be a toxic lipid species directly, but rather it is a feature of physiologic hypertrophy and may serve a cytoprotective role in lipid overload states. Moreover, induction of DGAT1 could be beneficial in the setting of excess heart accumulation of toxic lipids.
UR - http://www.scopus.com/inward/record.url?scp=73649094432&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.049817
DO - 10.1074/jbc.M109.049817
M3 - Article
C2 - 19778901
AN - SCOPUS:73649094432
SN - 0021-9258
VL - 284
SP - 36312
EP - 36323
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -