Abstract 12908: Inhibition of Hepatic Sulf2 in vivo Corrects Postprandial Dyslipidemia in Type 2 Diabetic Mice
Background Type 2 diabetes mellitus (T2DM) impairs hepatic clearance of atherogenic postprandial triglyceride-rich lipoproteins (TRL). We recently reported that livers from T2DM db/db mice overexpress SULF2, an enzyme that removes 6-O sulfate groups from heparan sulfate proteoglycans (HSPGs) and markedly suppresses uptake of TRLs by cultured hepatocytes.
Goal In the present study, we evaluated whether Sulf2 inhibition in vivo in T2DM mice could correct their postprandial dyslipoproteinemia.
Methods Selective second-generation antisense oligonucleotides (ASOs) targeting Sulf2 were constructed. T2DM mice were treated for 5 weeks with Sulf2 ASO (20 or 50 mg/kg per week), non-target ASO, or phosphate buffered saline (PBS). Lean db/m littermates served as controls. We studied the effect of Sulf2 antisense in vivo on hepatic HSPG sulfation, binding of VLDL to isolated primary hepatocytes, and most importantly, plasma triglyceride (TG) excursions following corn-oil gavage.
Results Sulf2 ASO administration to T2DM mice dose-dependently reduced hepatic Sulf2 mRNA expression (by up to 80%±5%; p<0.01), corrected SULF2 protein levels at the higher dose, and increased hepatic HSPG sulfation (p<0.05). Compared to control db/m hepatocytes, hepatocytes isolated from db/db mice after administration of the non-target ASO exhibited a significant impairment in VLDL binding that was entirely corrected in hepatocytes from db/db mice following treatment with the higher-dose Sulf2 ASO. Administration of Sulf2 ASO to T2DM mice lowered their random, non-fasting plasma TG levels by 50% (Sulf2 ASO: 150±24 mg/dL; non-target ASO: 290±123 mg/dL; p<0.05). Most importantly, Sulf2 ASO treatment of T2DM mice essentially flattened their plasma TG excursion after corn oil gavage. The incremental AUC was only 64±80 (mg/dL)•h in the Sulf2 ASO-treated T2DM mice, versus 1,400±1,000 (mg/dL)•h in T2DM mice given the non-target ASO (p<0.01).
Conclusion Inhibition of hepatic Sulf2 in T2DM mice normalizes the ability of their hepatocytes to bind VLDL and essentially abolishes postprandial hypertriglyceridemia. These findings provide a key proof-of-concept in vivo to support Sulf2 inhibition as an attractive strategy to improve metabolic dyslipidemia.
- © 2011 by American Heart Association, Inc.