Copyright © 2005, European Society of Cardiology
Changes in cardiac lipid metabolism during sepsis: The essential role of very low-density lipoprotein receptors
aDepartment of Organ Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
bThird Department of Internal Medicine, Faculty of Medical Science, University of Fukui, Fukui, Japan
cDepartment of Advanced Medical Technology and Development, BML Inc., Saitama, Japan
dInstitute of Biochemistry, National Yang-Ming University, Taipei, Taiwan
* Corresponding author. Tel./fax: +81 263 37 3193/+81 63 37 2573. Email address: masafumi{at}sch.md.shinshu-u.ac.jp
Objective: Sepsis accompanies myocardial dysfunction and dynamic alterations of cardiac metabolism. We have recently demonstrated that the very low-density lipoprotein receptor (VLDL-R), which is abundantly expressed in the heart, plays a key role in energy metabolism of the fasting heart. However, little is known about the function and regulation of the VLDL-R during sepsis. In the present study, we explored lipid accumulation and VLDL-R expression in the lipopolysaccharide (LPS)-stimulated heart in vivo and regulation of VLDL-R expression in vitro.
Methods and results: Electron microscopy and immunohistochemistry demonstrated that LPS significantly decreased both lipid accumulation and VLDL-R expression in the hearts of fasting mice. Treatment with LPS also downregulated VLDL-R in rat neonatal cardiac myocytes, and this downregulation was completely reversed by interleukin (IL)-1β receptor antagonist. IL-1β downregulated the expression of VLDL-R in a time- and dose-dependent manner and markedly reduced the uptake of DiI-labeled β-VLDL but not DiI-labeled low-density lipoprotein (LDL). Use of specific pharmacologic inhibitors and short interference RNA revealed that Hsp90 was required for IL-1β to downregulate VLDL-R expression.
Conclusions: These findings suggest that IL-1β is a principle mediator of changes in cardiac lipid and energy metabolism during sepsis through the downregulation of myocardial VLDL-R expression.
KEYWORDS Cytokines; Inflammation; Lipoproteins; Myocytes; Receptors
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