Deficiency of the Very Low-Density Lipoprotein (VLDL) Receptors in Streptozotocin-Induced Diabetic Rats: Insulin Dependency of the VLDL Receptor

Abstract

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-rich lipoproteins with high specificity. We examined the etiology of hyperlipidemia in the 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 d 21 and 28, with a dramatic decline in VLDL-R protein in skeletal muscle (>90%), heart (approximately 50%) and a loss of adipose tissues itself on d 28. The reduction of VLDL-R protein in skeletal muscle could not be explained simply by a decrease at the transcriptional level, because a dissociation between VLDL-R protein and mRNA expression was observed. The expression of LDL-R and LDL-R-related protein in liver showed no consistent changes. Furthermore, no effect on VLDL-triglyceride production in liver was observed in STZ rats. A decrease in postheparin plasma lipoprotein lipase activity started on d 7 and continued to d 28 at the 50% level even though severe hyperlipidemia was detected only on d 21 and 28. In rat myoblast cells, serum deprivation for 24 h induced a reduction in VLDL-R proteins. Insulin (10(-6) m), but not IGF-I (10 ng/ml), restored the decreased VLDL-R proteins by serum deprivation. These results suggest that the combination of VLDL-R deficiency and reduced plasma lipoprotein lipase activity may be responsible for severe hyperlipidemia in insulin-deficient diabetes.

Phosphatidylinositol 3-Kinase–Dependent Activation of Akt, an Essential Signal for Hyperthermia-Induced Heat-Shock Protein 72, Is Attenuated in Streptozotocin-Induced Diabetic Heart

“…Finally, insulin deficiency stimulates lipolysis in adipose tissue, increasing the delivery of free fatty acid from adipose tissue to liver and consequently, triglyceride production in liver. STZ-induced diabetic rats have shown increased serum triglyceride and free fatty acid levels (29,30). In disagreement, our STZ-induced diabetic rats showed lower serum concentrations of triglyceride and free fatty acid.…”

Impairment of nitrergic system and delayed gastric emptying in low density lipoprotein receptor deficient female mice

“…However, mice with STZ induced diabetes and LDL receptor defects often develop severe hyperlipidemia 20, 21. It has also been reported that the severe elevation of serum cholesterol and TG concentrations in STZ-induced diabetic rats 19. And it is a known fact that exaggerated postprandial hypertriglyceridemia is common in diabetic patients and this may also contribute for the development of gastroparesis 5…”

Lipoproteins: A Source of Cardiac Lipids

“…There is no evidence that the increased heart TG in the setting of diabetes is due to upregulation of lipoprotein receptors. In fact, diabetic hyperlipidemia reduces heart VLDLr protein [ 136 ] due to post-translational regulation. This change may represent a compensatory response that occurs in advanced stages of diabetes aiming to counterbalance cardiac lipid uptake and lipotoxicity that occur in diabetic hearts [ 137 ].…”