Insulin-dependent Diabetes Mellitus in Mice Does Not Alter Liver Heparan Sulfate

Abstract

Diabetes -associated hyperlipidemia is generally attributed to reduced clearance of plasma lipoproteins, especially remnant lipoproteins enriched in cholesterol and triglycerides. Hepatic clearance of remnants occurs via low density lipoprotein receptors and the heparan sulfate proteoglycan, syndecan-1. Previous studies have suggested alterations in heparan sulfate proteoglycan metabolism in rat and mouse diabetic models, consistent with the idea that diabetic dyslipidemia might be caused by alterations in proteoglycan expression in the liver. In this study we analyzed the content and composition of liver heparan sulfate in streptozotocin-induced insulin-deficient diabetic mice that displayed fasting hypertriglyceridemia and delayed clearance of dietary triglyceride-rich lipoproteins. No differences between normal and diabetic littermates in liver heparan sulfate content, sulfation, syndecan-1 protein levels, or affinity for heparin-binding ligands, such as apolipoprotein E or fibroblast growth factor-2, were noted. Decreased incorporation of [35 S]sulfate in insulin-deficient mice in vivo was observed, but the decrease was due to increased plasma inorganic sulfate, which reduced the efficiency of labeling of liver heparan sulfate. These results show that hyperlipidemia in insulin-deficient mice is not due to changes in hepatic heparan sulfate composition.Hypertriglyceridemia is a significant complication of insulindependent diabetes mellitus (IDDM) 2 that likely contributes to cardiovascular disease in affected individuals, but its cause remains unknown (1-3). Insulin deficiency suppresses hepatic triglyceride production (4, 5), suggesting that increased plasma triglyceride levels might result from decreased catabolism of triglyceride-rich lipoproteins (TRL). In various diabetic models delayed TRL remnant clearance has been attributed to altered expression of heparan sulfate proteoglycans (HSPGs) in the liver (6 -14).We recently showed that mutant mice lacking the plasma membrane HSPG, syndecan-1, exhibit hypertriglyceridemia due to delayed clearance of TRL remnants from the circulation associated with reduced VLDL binding, uptake, and degradation in isolated hepatocytes (15). Furthermore, mice with undersulfated liver heparan sulfate have the same phenotype (16,17). One of mutants lacked the enzyme N-acetylglucosamine N-deacetylase/N-sulfotransferase 1 (Ndst1), a biosynthetic enzyme that regulates the overall level of sulfation of heparan sulfate glycosaminoglycans. In vivo studies have suggested that IDDM causes reduced expression of Ndst1 (6,10,11,13,14,18), leading to the hypothesis that hypertriglyceridemia was caused by undersulfated heparan sulfate in the liver.In this work, we show that mice with IDDM exhibit reduced [ 35 S]sulfate incorporation into hepatic heparan sulfate. However, the reduction was caused by changes in plasma sulfate concentration after the onset of diabetes rather than any change in heparan sulfate biosynthesis. The application of mass spectrometry showed that hepatic heparan sulf...

Lipolysis, and Not Hepatic Lipogenesis, Is the Primary Modulator of Triglyceride Levels in Streptozotocin-Induced Diabetic Mice

“…Similar to humans with either T1DM or T2DM, STZ-induced diabetes in C57BL/6 mice led to a significant increase in plasma TG levels. This observation was similar to that described by others 22, 23 . The primary lipoprotein abnormality in human diabetes is an increase in VLDL, which was reproduced in our STZ-treated mice.…”

Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism

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Reduced Sulfation of Chondroitin Sulfate but Not Heparan Sulfate in Kidneys of Diabetic db/db Mice

“…**p<0.01. HS in mice made diabetic by streptozotocin injection (Bishop et al 2010). Although our analyses concerned a different tissue, it is interesting to note that HS changes were detected neither in liver nor kidney, two organs affected in insulin-dependent diabetic mice (type 1 diabetes) and mice used as a model for type 2 diabetes.…”