Type 2 diabetes in mice induces hepatic overexpression of sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins

Accelerated atherosclerotic cardiovascular disease remains the major cause of death in patients with diabetes and related syndromes.1 Atherosclerosis arises from the retention of cholesterol-rich, apolipoprotein-B (apoB)-containing lipoproteins within the vessel wall.2 Importantly, diabetic patients suffer from a unique and typically neglected aspect of cardiovascular risk, namely, the striking persistence of postprandial apoB-lipoproteins, called ‘remnants,’ in their plasma after each meal. A major cause is a defect in hepatic clearance of these harmful particles.3-6 A conspicuous impediment in this area had been our ignorance regarding pathways for remnant uptake into liver. Over a quarter century ago, hepatic uptake of remnants was shown to occur independently of LDL receptors.7 This realization launched a long, difficult search for the responsible molecules. Our work8 and others’9-12 implicated heparan sulfate proteoglycans (HSPGs) as remnant lipoprotein receptors (reviewed by5, 6, 13). Each HSPG molecule consists of a protein strand onto which the cell assembles sugar polymers, called heparan sulfate, that we showed could capture lipoproteins. Thus, the ligand-binding domains of these molecules are carbohydrate, not polypeptide. The liver contains several different species of HSPGs, from which our laboratory identified syndecan-1 as a strong candidate to participate in remnant lipoprotein clearance, based on its abundance along the sinusoidal surface of hepatic parenchymal cells and our finding that it directly mediates endocytosis of lipoproteins.13-15 These results were recently extended by the demonstration that syndecan-1 knock-out mice exhibit substantially impaired remnant lipoprotein clearance.16 Thus, the syndecan-1 HSPG is a major hepatic receptor for remnant lipoproteins.13, 15, 16 In the current study, we focused on type 2 diabetes (T2DM), a disease of considerable and increasing clinical impact.1, 5, 6 In T2DM and other syndromes of insulin resistance, the proteoglycans from liver17 and elsewhere18 exhibit subnormal charge density17, decreased heparan sulfation17, 18, and impaired binding to model remnant lipoproteins.17 Hyperphagic mice provide a suitable animal model, because they mimic humans who overeat and thereby develop the same downstream consequences, including obesity, insulin resistance, T2DM, and impaired remnant catabolism by the liver.19 To assess the effects of T2DM on the roughly 50 genes involved in HSPG assembly and disassembly, we used a highly annotated glycomic microarray20 to compare hepatic expression profiles in hyperphagic mice versus controls. Surprisingly, these arrays identified just one gene whose dysregulation would impair HSPG structure: the heparan sulfate glucosamine-6-O-endosulfatase-2 (Sulf2). This gene encodes an enzyme that degrades cell-surface HSPGs by removing 6-O-sulfates. The SULF2 enzyme has been studied so far only in the context of growth factor and morphogen signaling,21, 22 with no prior suspicion of a role in lipoprotein biology or diabetes.5, 6 Preliminary reports of this work were presented at the International Symposium on Atherosclerosis (June 2009, Boston, USA)23 and at the American Heart Association Scientific Sessions (November 2009, Orlando, USA).24