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Abstract

Altered lipoprotein lipase regulation associated with diabetes leading to the development of hypertriglyceridemia might be attributed to possible changes in content and the fine structure of heparan sulfate and its associated lipoprotein lipase. Adipocyte cell surface is the primary site of synthesis of lipoprotein lipase and the enzyme is bound to cell surface heparan sulfate proteoglycans via heparan sulfate side chains. In this study, the effect of diabetes on the production of adipocyte heparan sulfate and its sulfation (especially N-sulfation) were examined. Mouse 3T3-L1 adipocytes were exposed to high glucose (25 mM) and low glucose (5.55 mM) in the medium and cell-associated heparan sulfate was isolated and characterized. A significant decrease in total content of heparan sulfate was observed in adipocytes cultured under high glucose as compared to low glucose conditions. The degree of N-sulfation was-assessed through oligosaccharide mapping of heparan sulfate after chemical cleavages involving low pH (1.5) nitrous acid and hydrazinolysis/high pH (4.0) nitrous acid treatments; N-sulfation was found to be comparable between the adipocyte heparan sulfates produced under these glucose conditions. The activity and message levels for N-deacetylase/N-sulfotransferase, the enzyme responsible for N-sulfation in the biosynthesis of heparan sulfate, did not vary in adipocytes whether they were exposed to low or high glucose. While most cells or tissues in diabetic situations produce heparan sulfate with low-charge density concomitant with a decrease in N-sulfation, adipocyte cell system is an exception in this regard. Heparan sulfate from adipocytes cultured in low glucose conditions binds to lipoprotein lipase by the same order of magnitude as that derived from high glucose conditions. It is apparent that adipocytes cultured under high glucose conditions produce diminished levels of heparan sulfate (without significant changes in N-sulfation). In conclusion, it is possible that the reduction in heparan sulfate in diabetes could contribute to the decreased levels of heparan sulfate associated lipoprotein lipase, leading to diabetic hypertriglyceridemia.

No Change in Glomerular Heparan Sulfate Structure in Early Human and Experimental Diabetic Nephropathy

“…Despite this extensive approach, only one significant diabetes-induced change was observed, namely a ϳ60% increase in N-deacetylase enzymatic activity, which, however, was not accompanied by a change in glomerular HS N-sulfation. A number of publications describe a diabetes-induced inhibition of HS NDST and/or HS N-sulfation, with conflicting results (33)(34)(35)(36)(37)(38)(39)(40). Our data indicate that determination of enzyme activity does not safely predict changes in structure or sulfation of the HS polysaccharide.…”

Heparan Sulfate: A Regulator of White Adipocyte Differentiation and of Vascular/Adipocyte Interactions

“…These compounds compete for the attachment sites on core proteins with the result of producing HSPGs with fewer HS chains, hence decreasing sulfation. The observation that glucose levels have a direct effect on HS chain structure suggests that modifying glucose levels in culture media may also result in the modification of sulfation levels [ 37 , 40 ]. There are also more subtle ways that HS sulfation can be modified.…”

“…This process may also occur when mature adipocytes become hypertrophic. In addition, 3T3-L1 cells grown under high glucose conditions exhibit a reduction in cell surface sulfation and a release of bound LPL [ 37 ]. In short, HS plays a role in glucose metabolism.…”