Abstract 5921: Metabolic Factors in Type 2 Diabetes Augment Hepatocyte Expression of SULF2, a Novel Suppressor of Remnant Lipoprotein Uptake
Type 2 diabetes (T2DM) and related conditions substantially impair hepatic clearance of atherogenic postprandial remnant lipoproteins. Our work (JBC 267:13284, 1992) and others’ implicated heparan sulfate proteoglycans (HSPGs) as remnant lipoprotein receptors (reviewed in JCI 118:3247, 2008). We recently reported that T2DM in db/db mice induces hepatic overexpression of the heparan sulfate glucosamine-6-O-endosulfatase-2 (SULF2), an enzyme that degrades cell-surface and matrix HSPGs by removing 6-O-sulfate groups (ISA, June 2009, Boston, USA). We also reported that SULF2 impedes HSPG-mediated catabolism of model remnant lipoproteins. In the current study, we investigated the effects of three metabolic factors, insulin, adiponectin, and advanced glycosylation end-products (AGEs), on hepatocyte expression of SULF2. Exposure of McArdle 7777 (McA) rat hepatoma cells to 3nM insulin for 24h suppressed cellular SULF2 protein by 80%±5% (p<0.01). Likewise, a 4-h normoglyce-mic, hyperinsulinemic clamp suppressed SULF2 protein in rat livers by 55%±5% (p<0.05). Addition of adiponectin (6μg/ml) to cultured McA cells for 24h suppressed SULF2 levels by 90%±5% (p<0.01). Additionally, livers from adiponectin knock-out mice exhibited substantially increased levels of SULF2 protein, which was suppressed by 5d of adiponectin injections. Exposure of McA cells to AGEs (200μg/ml for 24h) caused a 20-fold induction of Sulf2 mRNA and a 10-fold induction of SULF2 protein. Functionally, suppression of SULF2 in McA cells by insulin, adiponectin or siRNA knock-down significantly increased binding, endocytosis, and lysosomal degradation of model remnant lipoproteins(I125-mLDL). Exposure of McA cells to AGEs impaired catabolism of model remnant lipoproteins by 70%±5% (P <0.01), and this effect was reversed by SULF2 knock-down. Taken together, we conclude that insulin resistance, hypoadiponectinemia, and AGEs induce hepatic overexpression of SULF2, thereby providing a novel molecular mechanism that contributes to atherogenic postprandial dysli-poproteinemia in T2DM and related disorders.