Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice

Abstract

We used wild-type (WT) mice and mice engineered to express either apoB-100 only (B100 mice) or apoB-48 only (B48 mice) to examine the effects of streptozotocin-induced diabetes (DM) on apoB-100-and apoB-48-containing lipoproteins. Plasma lipids increased with DM in WT mice, and fat tolerance was markedly impaired. Lipoprotein profiles showed increased levels and cholesterol enrichment of VLDL in diabetic B48 mice but not in B100 mice. C apolipoproteins, in particular apoC-I in VLDL, were increased. To investigate the basis of the increase in apoB-48 lipoproteins in streptozotocin-treated animals, we characterized several parameters of lipoprotein metabolism. Triglyceride and apoB production rates were normal, as were plasma lipase activity, VLDL glycosaminoglycan binding, and VLDL lipolysis. However, β-VLDL clearance decreased due to decreased trapping by the liver. Whereas LRP activity was normal, livers from treated mice incorporated significantly less sulfate into heparan sulfate proteoglycans (HSPG) than did controls. Hepatoma (HepG2) cells and endothelial cells cultured in high glucose also showed decreased sulfate and glucosamine incorporation into HSPG. Western blots of livers from diabetic mice showed a decrease in the HSPG core protein, perlecan. Delayed clearance of postprandial apoB-48-containing lipoproteins in DM appears to be due to decreased hepatic perlecan HSPG.

Changes in Matrix Proteoglycans Induced by Insulin and Fatty Acids in Hepatic Cells May Contribute to Dyslipidemia of Insulin Resistance

“…If a similar situation existed in vivo, it could contribute to increased circulating remnant particles in obese Zucker rats. In a type 1 diabetes model, Ebara et al (32) found delayed catabolism of apoB-48 lipoproteins because of decreased HS PG production in diabetic mice. They suggested that the effect was attributable to the effects of hyperglycemia on matrix production.…”

Diabetic Vascular Disease

“…In contrast apoE knockout mice develop elevations of cholesterol with STZ diabetes. The reasons for the hypercholesterolemia in this model were studied by Ebara et al 57 Catabolism of remnant lipoproteins was reduced in STZtreated apoE knockout mice and this effect was attributed to a reduction in liver trapping associated with reduced proteoglycan production and loss of normal lipoprotein receptor uptake pathways.…”

Diabetic dyslipidaemia: from basic research to clinical practice*

“…HSPG, LPL, hepatic lipase as well as apo E can act as bridging proteins and thus modulate the removal of remnants. Recently reduced synthesis of HSPG core protein perlican was reported in streptosotozin diabetic mice together with concomitant delayed clearance of apo B 48 containing lipoproteins [90].…”