Abstract 16934: UC1002, a Carboxyl Ester Lipase Inhibitor, Raises HDL in CETP Transgenic Mice and Increases Reverse Cholesterol Transport, and Also Lowers LDL and VLDL in Mice Fed Western Diet
Background: Raising HDL and increasing reverse cholesterol transport (RCT) are believed to lower cardiovascular risk independently of decreasing LDL. We recently documented increased RCT in carboxyl ester lipase (CEL) knockout mice by a mechanism that involves both increased biliary transport of HDL cholesteryl ester and lack of cholesteryl ester hydrolysis in intestine. We have also shown that lack of CEL in mice expressing CETP raises serum HDL due to increased hepatic production. Objective: To test the efficacy of CEL inhibitor, UC1002, with respect to increasing RCT and raising HDL in CETP transgenic mice; to test the efficacy of UC1002 in reversing hyperlipidemia in Western diet-fed CETP transgenic mice.
Methods: Wild type C57BL/6 mice or C57BL/6 mice with a CETP transgene were given UC1002 daily for 2 weeks in chow at doses of 50-150 mg/kg b.w. (n = 6-12). Sterol excretion was measured before and after treatment or was measured in control groups fed normal chow. HDL was measured by heparin/Mn precipitation or by FPLC fractionation. A cohort of CETP transgenic mice heterozygous for LDL receptor deletion was fed Western diet for 16 weeks followed by 6 weeks of diet with UC1002+simvastatin, statin alone, or no drug treatment (6 per group). At the end of the test period, serum lipids, lipoproteins, and liver enzymes were quantified, and tissues harvested.
Results: Maximum efficacy was achieved at 100 mg/kg of UC1002, which increased fecal sterol excretion by 60% (P = 0.005), and, In CETP mice, raised HDL by 26% (44.4 ± 6.5% to 56.0 ± 3.2% of plasma cholesterol, P = 0.005). In Western diet fed CETP/LDLR+/− mice, UC1002+statin reduced triglycerides 54% (P < 0.001), reduced LDL 26% (P = 0.002), and raised HDL 14% (P = 0.003) compared to statin alone. Serum ALT was reduced 67% (P = 0.016) by the combined treatment compared to no treatment. Liver histology indicated ∼50% less necrosis and macrosteatosis with both treatment regimens. No pathology was associated with UC1002.
Conclusions: CEL inhibitor UC1002 improves reverse cholesterol transport and serum lipoprotein profiles in CETP mice with diet-induced dyslipidemia similar to that in humans. Thus, targeted CEL inhibition may be a novel strategy for treatment of hyperlipidemia to decrease the risk of cardiovascular disease.
- © 2011 by American Heart Association, Inc.