Effect of up-regulating individual steps in the reverse cholesterol transport pathway on reverse cholesterol transport in normolipidemic mice

Cholesterol acquired by extrahepatic tissues (from de novo synthesis or lip oproteins) is returned to the liver for excretion in a process called rever se cholesterol transport (RCT). We undertook studies to determine if RCT co uld be enhanced by up-regulating individual steps in the RCT pathway. Overe xpression 7 alpha -hydroxylase, Scavenger receptor B1, lecithin:cholesterol acyltransferase (LCAT), or apoA-I in the liver did not stimulate cholester ol efflux from any extrahepatic tissue, In contrast, infusion of apoA-I pho spholipid complexes (rHDL) that resemble nascent HDL markedly stimulated ch olesterol efflux from tissues into plasma. Cholesterol effluxed to rHDL was initially unesterified but by 24 h this cholesterol was largely esterified and had shifted to normal HDL (in mice lacking cholesteryl ester transfer protein) or to apoB containing lipoproteins (in cholesteryl ester transfer protein transgenic mice). Most of the cholesterol effluxed into plasma in r esponse to rHDL came from the liver. However, an even greater proportion of effluxed cholesterol was cleared by the liver resulting in a transient inc rease in liver cholesterol concentrations. Fecal sterol excretion was not i ncreased by rHDL. Thus, although rHDL stimulated cholesterol efflux from mo st tissues and increased net cholesterol movement from extrahepatic tissues to the liver, cholesterol flux through the entire RCT pathway was not incr eased.