Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58

被引：60

作者：

Zierler, Kathrin A. ^{[1
]}

Jaeger, Doris ^{[1
]}

Pollak, Nina M. ^{[1
]}

Eder, Sandra ^{[1
]}

Rechberger, Gerald N. ^{[1
]}

Radner, Franz P. W. ^{[1
]}

Woelkart, Gerald ^{[2
]}

Kolb, Dagmar ^{[3
]}

Schmidt, Albrecht ^{[4
]}

Kumari, Manju ^{[1
]}

Preiss-Landl, Karina ^{[1
]}

Pieske, Burkert ^{[4
]}

Mayer, Bernd ^{[2
]}

Zimmermann, Robert ^{[1
]}

Lass, Achim ^{[1
]}

Zechner, Rudolf ^{[1
]}

Haemmerle, Guenter ^{[1
]}

机构：

[1] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria

[2] Graz Univ, Dept Pharmacol & Toxicol, A-8010 Graz, Austria

[3] Med Univ Graz, Med Res Ctr, A-8036 Graz, Austria

[4] Med Univ Graz, Dept Cardiol, Dept Internal Med, A-8036 Graz, Austria

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2013年 / 288卷 / 14期

基金：

奥地利科学基金会;

关键词：

ADIPOSE TRIGLYCERIDE LIPASE; CHANARIN-DORFMAN-SYNDROME; LIPID STORAGE DISEASE; CELLULAR FAT STORES; ENERGY-METABOLISM; SKELETAL-MUSCLE; LYSOPHOSPHATIDIC ACID; INSULIN SENSITIVITY; PPAR-ALPHA; CGI-58;

D O I：

10.1074/jbc.M112.420620

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：

Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL.

引用

页码：9892 / 9904

页数：13

共 42 条

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