2007 Fiscal Year Final Research Report Summary
Function of hormone-sensitive lipase in the development of diabetic cardiomyopathy
| Project/Area Number |
17590923
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | University of Fukui |
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Principal Investigator |
SUZUKI Jinya University of Fukui, Faculty of Medical Sciences, Assistant Professor (20293417)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Sadao University of Fukui, Hospital, Lecturer (50303376)
KOIZUMI Tsutomu University of Fukui, Centers for Advanced Research Support, Associate Professor (40126579)
ISHIBASHI Shun Jichi Medical University, School of Medicine, Professor (90212919)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Diabetic Cardiomvonathv / Steatosis / Lipase / Cardiomyopathy |
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| Research Abstract |
Study 1: Function of hormone-sensitive lipase in diabetic cardiomyopathy
We sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL-overexpression were generated and hearts were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wildtype (Wt) hearts after 3 weeks of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac lipid peroxide content was 2-fold lower in Tg hearts than Wt hearts. The mRNA expressions for PPARα, genes for triacylglycerol synthesis were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Diabetic Wt hearts showed interstitial fibrosis. Since HSL-overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.
Study 2: Function of hormone-sensitive lipase in cardiac energy metabolism
We investigated how disruption of HSL affects cardiac energy metabolism in response to fasting and refeeding. HSL-KO mice and wildtype (Wt) littermates were fasted for 24 h followed by-6h of refeeding to study cardiac metabolism. Plasma FA concentration in Wt mice was elevated 2-fold with fasting, while KO mice lacked this elevation. Cardiac FA uptake was 2-fold lower in KO mice than Wt mice during fasting. Cardiac VLDL uptake and lipoprotein lipase (LPL) activity was 2-fold higher in KO mice during fasting. The KO hearts showed undetectable activity of neutral cholesteryl esterase and 40% lower non-LPL triglyceride lipase activity in refed conditions, and overt steatosis. Adipose and cardiac HSL coordinately control cardiac energy metabolism to maintain normal cardiac function and steatosis in response to altering food availability.
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[Journal Article] Glucose deprivation accelerates VLDL receptor-mediated TG-rich lipoprotein uptake by AMPK activation in skeletal muscle cells2008
Author(s)
Zenimaru, Y., Takahashi, S., Takahashi, M., Yamada, K., Iwasaki, T., Hattori, H., Imagawa, M., Ueno, M., Suzuki, J., Miyamori, I
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Journal Title
Biochem Biophys Res Commun 368
Pages: 716-722
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Deficiency of the very low-density lipoprotein (VLDL) receptors in streptozotocin-induced diabetic rats : insulin dependency of the VLDL receptor2005
Author(s)
Iwasaki, T., Takahashi, S., Takahashi, M., Zenimaru, Y., Kujiraoka, T., Ishihara, M., Nagano, M., Suzuki, J., Miyamori, I., Naiki, H., Sakai, J., Fujino, T., Miller, NE., Yamamoto, TT., Hattori, H
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Journal Title
Endocrinology 146
Pages: 3286-3294
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Interleukin-lbeta attenuates beta-very low-density lipoprotein uptake and its receptor expression in vascular smooth muscle cells2005
Author(s)
Takahashi, M., Takahashi, S., Suzuki, C., Jia, L., Morimoto, H., Ise, H., Iwasaki, T., Hattori, H., Suzuki, J., Miyamori, I., Kobayashi, E., Ikeda, U
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Journal Title
J Mol Cell Cardiol 38
Pages: 637-646
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice
Author(s)
Ueno, M., Suzuki, J., Zenimaru, Y., Takahashi, S., Koizumi, T., Noriki, S., Yamaguchi, O., Otsu, K., Shen, WJ., Kraemer, FB., Miyamori, I
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Journal Title
Am J Physiol Endocrinol Metab (in press)
Description
「研究成果報告書概要(欧文)」より
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