Abstract 19177: An Orally Administered Small Molecule That Inhibits Hepatic Sulfatase-2 Expression In Vivo: A Novel Strategy to Correct Diabetic Dyslipoproteinemia With Implications for Residual Atherosclerotic Cardiovascular Disease (ASCVD) Risk

Introduction: Patients treated with optimal statin therapy and even PCSK9 inhibitors exhibit considerable residual risk for ASCVD events. Residual ASCVD risk may occur, in part, because these medications only slightly lower plasma levels of cholesterol- and triglyceride-rich remnant apoB-lipoproteins (C-TRLs). The atherometabolic syndrome and type 2 diabetes (T2DM) increase plasma levels of C-TRLs, owing largely to a defect in hepatic clearance. We identified syndecan-1 as a major receptor for uptake of C-TRLs by hepatocytes. Moreover, we showed that obesity and T2DM cause hepatic overexpression of sulfatase-2 (SULF2) and that SULF2 inhibits hepatic disposal of C-TRLs in human T2DM dyslipoproteinemia. Thus, SULF2 is a key target in ASCVD. Still, no small molecule has been identified that can normalize hepatic SULF2 expression in diabetes. Hypothesis: A novel small molecule, gemcabene, that lowers plasma apoB-lipoprotein concentrations in mice and in humans may regulate SULF2 in the liver. Methods: We used...