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Submitted on January 13, 2005
Accepted on April 18, 2005
Insulin Dependency of the VLDL Receptor and LPL, and Partial Etiology of Insulin-Deficient Diabetic Hyperlipidemia; Department of Advanced Medical Technology and Development (T.I., T.K., M. I., M. N., H.H.), BML, Inc., Kawagoe, Japan; Third Department of Internal Medicine (S.T., Y.Z., J.S., I. M.), Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Cardiovascular Surgery (M.T.), Hiratsuka Kyosai Hospital, Hiratuka, Japan; Second Department of Pathology (H. N.), University of Fukui, Fukui, Japan; Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology (J.S.), University of Tokyo, Komaba, and Exploratory Research for Advanced Technology of Japan Science and Technology Corporation (J.S.), Aomi, Japan; Department of Bioscience (T.F.), Integrated Center for Science, Ehime University, Shigenobu, Japan; Department of Cardiovascular Biochemistry, St Barts and the Royal London School of Medicine, (N.E.M.), London, UK; Center for Advanced Genome Research, Institute of Aging, Development and Cancer (T.T.Y.), Tohoku University, Sendai, Japan
* To whom correspondence should be addressed. E-mail: sadaost{at}fmsrsa.fukui-med.ac.jp.
Hyperlipidemia is a common feature of diabetes and is related to cardiovascular disease. The very low-density lipoprotein receptor (VLDL-R) is a member of the low-density lipoprotein receptor (LDL-R) family. It binds and internalizes triglyceride (TG)-rich lipoproteins with high specificity. We examined the etiology of hyperlipidemia in insulin-deficient state. VLDL-R expression in heart and skeletal muscle were measured in rats with streptozotocin (STZ)-induced diabetes. STZ rats showed severe hyperlipidemia on day 21 and 28 with a dramatic decline in VLDL-R protein in skeletal muscle (>90%), heart (about 50%) and a loss of adipose tissues itself on day 28. The reduction of VLDL-R protein in skeletal muscle could not be explained simply by a decrease at transcriptional level, as the dissociation between VLDL-R protein and mRNA expression was observed. The expression of the LDL-R and LDL receptor-related protein (LRP1) in liver showed no consistent changes. Furthermore, no effect on VLDL-TG production in liver was observed in STZ rats. Post-heparin plasma lipoprotein lipase (LPL) activity was started to reduce on day 7 and continued to on day 28 at 50% level even though severe hyperlipidemia was detected only on day 21 and 28. In rat myoblast cells, serum deprivation for 24 h induced reduction of the VLDL-R proteins. Insulin (10-6 M) but not IGF-1 (10ng/ml) recovered the decreased VLDL-R proteins by serum deprivation. These results suggest that the combination of VLDL-R deficiency and reduced plasma LPL activity may be responsible for severe hyperlipidemia in insulin-deficient diabetes.
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