Apolipoprotein Cl (apoCl) has been suggested to influence HDL metabolism by activation of LCAT and inhibition of HL and CETP. However, the effect of apoCl on scavenger receptor BI (SR-Bl)-mediated uptake of HDL-cholesteryl esters (CE), as well as the net effect of apoCl on HDL metabolism in vivo is unknown. Therefore, we evaluated the effect of apoCl on the SR-BI-mediated uptake of HDL-CE in vitro and determined the net effect of apoCI on HDL metabolism in mice. Enrichment of HDL with apoCI close-dependently decreased the SR-BI-dependent association of [H-3]CE-labeled HDL with primary murine hepatocytes, similar to the established SR-BI-inhibitors apoCIII and oxLDL. ApoCI deficiency in mice gene dose-dependently decreased HDL-cholesterol levels. Adenovirus-mediated expression of human apoCI in mice increased HDL levels at a low dose and increased the HDL particle size at higher doses. We conclude that apoCI is a novel inhibitor of SR-BI in vitro and increases HDL levels in vivo. (c) 2008 Elsevier Inc. All rights reserved.