学科主题基础医学
Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure
Liu, Li1,3; Trent, Chad M.1; Fang, Xiang1,7; Son, Ni-Huiping1; Jiang, HongFeng1; Blaner, William S.1; Hu, Yunying1; Yin, Yu-Xin3; Farese, Robert V., Jr.4,5,6; Homma, Shunichi2; Turnbull, Andrew V.8; Eriksson, Jan W.8,9; Hu, Shi-Lian7; Ginsberg, Henry N.1; Huang, Li-Shin1; Goldberg, Ira J.1,2,10
关键词Animal Model Cardiac Metabolism Ceramide Diacylglycerol Heart Failure Lipid Lipotoxicity Metabolism Signal Transduction
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
2014-10-24
DOI10.1074/jbc.M114.601864
289期:43页:29881-29891
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]KINASE-C-ALPHA ; INSULIN-RESISTANCE ; SKELETAL-MUSCLE ; IN-VIVO ; TRIACYLGLYCEROL SYNTHESIS ; TRIGLYCERIDE SYNTHESIS ; OBESITY RESISTANCE ; HEPATIC STEATOSIS ; SYNTHESIS ENZYME ; MICE
英文摘要

Background: Total body DGAT1 mice have no cardiac phenotype. Results: Cardiomyocyte DGAT1 knock-out mice have increased mortality and accumulation of potentially toxic lipids, which were corrected by intestinal DGAT1 deletion and GLP-1 receptor agonists. Conclusion: Cardiomyocyte DGAT1 deletion produces heart dysfunction and lipid abnormalities. Significance: Lipotoxicity in the heart can be alleviated by changes in intestinal metabolism.

Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis, the conversion of diacylglycerol (DAG) to triglyceride. Dgat1(-/-) mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function, we created cardiomyocyte-specific DGAT1 knock-out (hDgat1(-/-)) mice. hDgat1(-/-) mouse hearts had 95% increased DAG and 85% increased ceramides compared with floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide increased 5-fold in hDgat1(-/-) hearts, and fractional shortening (FS) was reduced. This was associated with increased expression of peroxisome proliferator-activated receptor and cluster of differentiation 36. We crossed hDgat1(-/-) mice with previously described enterocyte-specific Dgat1 knock-out mice (hiDgat1(-/-)). This corrected the early mortality, improved FS, and reduced cardiac ceramide and DAG content. Treatment of hDgat1(-/-) mice with the glucagon-like peptide 1 receptor agonist exenatide also improved FS and reduced heart DAG and ceramide content. Increased fatty acid uptake into hDgat1(-/-) hearts was normalized by exenatide. Reduced activation of protein kinase C (PKC), which is increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.

语种英语
WOS记录号WOS:000344370800032
项目编号HL45095 ; HL73029 ; UL1 TR000040 ; 2010CB912202 ; 30930021
资助机构National Institutes of Health from the NHLBI ; National Center for Advancing Translational Sciences ; Heritage Affiliate of the American Heart Association ; Department of Human Resources and Social Security of Anhui Province ; Anhui Provincial Hospital ; China National Major Scientific Program (973 Project) ; National Natural Science Foundation of China
引用统计
被引频次:22[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/66722
专题北京大学基础医学院_北京大学系统生物医学研究所
北京大学基础医学院
作者单位1.Columbia Univ Coll Phys & Surg, Div Prevent Med & Nutr, New York, NY 10032 USA
2.Columbia Univ Coll Phys & Surg, Div Cardiol, New York, NY 10032 USA
3.Peking Univ, Inst Syst Biomed, Hlth Sci Ctr, Beijing 100083, Peoples R China
4.Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA
5.Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA
6.Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA
7.Anhui Med Univ, Affiliated Prov Hosp, Dept Geriatr, Hefei 230001, Peoples R China
8.Astra Zeneca Co, S-43150 Molndal, Sweden
9.Uppsala Univ, Dept Med Sci, S-75105 Uppsala, Sweden
10.NYU, Langone Sch Med, Div Endocrinol Diabet & Metab, New York, NY 10016 USA
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Liu, Li,Trent, Chad M.,Fang, Xiang,et al. Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2014,289(43):29881-29891.
APA Liu, Li.,Trent, Chad M..,Fang, Xiang.,Son, Ni-Huiping.,Jiang, HongFeng.,...&Goldberg, Ira J..(2014).Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure.JOURNAL OF BIOLOGICAL CHEMISTRY,289(43),29881-29891.
MLA Liu, Li,et al."Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure".JOURNAL OF BIOLOGICAL CHEMISTRY 289.43(2014):29881-29891.
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