HDL biology
The novel SR-BI inhibitor ITX5061 raises HDL cholesterol by 20% in humans and reduces atherosclerosis in mice regardless of CETP expression (Arterioscler Thromb Vasc Biol 2009)
Original title: Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor
ITX5061, initially characterized as a p38 MAPK inhibitor, increased HDL cholesterol by 20% in hypertriglyceridemic humans with low HDL levels, moderately increased apoA-I, and did not affect VLDL/LDL cholesterol or triglycerides. ITX5061 also increased HDL cholesterol in wild-type and human apoA-I transgenic mice, decreasing the fractional catabolic rate and hepatic uptake of HDL cholesteryl ester, and inhibited SR-BI-dependent uptake of HDL cholesteryl ester in transfected cells, but failed to raise HDL cholesterol in SR-BI-deficient mice. Given to atherogenic-diet-fed Ldlr+/- mice with or without cholesteryl ester transfer protein (CETP) expression for 18 weeks, ITX5061 reduced early atherosclerotic lesions in the aortic arch by 40% (P < 0.05) in both control and CETP-expressing groups.
Original abstract
Objective: Increasing HDL levels is a potential strategy for the treatment of atherosclerosis.
Methods And Results: ITX5061, a molecule initially characterized as a p38 MAPK inhibitor, increased HDL-C levels by 20% in a human population of hypertriglyceridemic subjects with low HDL levels. ITX5061 also moderately increased apoA-I but did not affect VLDL/LDL cholesterol or plasma triglyceride concentrations. ITX5061 increased HDL-C in WT and human apoA-I transgenic mice, and kinetic experiments showed that ITX5061 decreased the fractional catabolic rate of HDL-CE and reduced its hepatic uptake. In transfected cells, ITX5061 inhibited SR-BI-dependent uptake of HDL-CE. Moreover, ITX5061 failed to increase HDL-C levels in SR-BI(-/-) mice. To assess effects on atherosclerosis, ITX5061 was given to atherogenic diet-fed Ldlr(+/-) mice with or without CETP expression for 18 weeks. In both the control and CETP-expressing groups, ITX5061-treated mice displayed reductions of early atherosclerotic lesions in the aortic arch -40%, P<0.05), and a nonsignificant trend to reduced lesion area in the proximal aorta.
Conclusions: Our data indicate that ITX5061 increases HDL-C levels by inhibition of SR-BI activity. This suggests that pharmacological inhibition of SR-BI has the potential to raise HDL-C and apoA-I levels without adverse effects on VLDL/LDL cholesterol levels in humans.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.