XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
Reverse cholesterol transport (RCT) is a fundamental protective process of atherogenesis and a promising pharmacological target for future therapies. The discovery and elucidation of the role in RCT of apolipoprotein-cell interaction, ABC1, LXRs and SR-BI represent a turning point in this field.

Stockholm, Sweden -- Reverse cholesterol transport (RCT) is a fundamental protective process of atherogenesis and therefore a promising pharmacological target for future therapies. However, our knowledge of the mechanisms and cellular structures responsible for RCT modulation are limited. Recently several important data on this process have been obtained and a turning point on this field can be envisioned. In this workshop, Dr. S. Yokoyama (Nagoya City University Medical School, Japan) reported on the role of apolipoprotein-cell interaction as a key mechanism in determining both cellular cholesterol efflux and HDL plasma levels. ApoA-I interaction with cells requires a cell binding that is stimulated by cAMP and inhibited by probucol. Consistent with Dr. Yokoyama's hypothesis, in probucol-treated mice both cholesterol efflux and apoA-I binding are reduced concomitantly with HDL levels. This effect is achieved without affecting well-known structures involved in HDL metabolism, including the most recent ABC1. Dr. Yokoyama also suggested that caveolin-1 is involved in apoA-I-mediated cholesterol-efflux.

The important role of ABC1 in facilitating the interaction of apoA-I with cholesterol-loaded macrophages was reminded by Dr. A.R. Tall (Columbia University, New York, U.S.A.). He showed that ABC1 transfected cells had higher cholesterol efflux. Dr. Tall also underlined the importance in RCT of cholesteryl ester transfer protein (CETP) and of cyp7a, the enzyme regulating the conversion of cholesterol into bile acids. All of these factors are induced by hydroxysterol-activated transcription factors (LXRs), said Dr. Tall. This class of nuclear receptor may therefore represent an important regulatory target of RCT.

Dr. M.C. Phillips (Children's Hospital of Philadelphia, U.S.A.) focused on cell surface events describing the importance of the scavenger receptor class B, type I (SR-BI) in mediating both the delivery to and removal of cholesterol by HDL from the cell. In particular HDL cholesteryl ester (HDL-CE) selective uptake by cells occurs between the bound HDL and plasma membrane through a non-aqueous channel formed by the extracellular domains of SR-BI. The interaction of SR-BI with lipoproteins is not unique for HDL, but involves particles containing several classes of apolipoproteins including LDL. This multi-ligand characteristic is due to the ability of SR-BI to bind the amphipatic alpha helix a common structural motif of apolipoproteins, explained Dr. Phillips. Using SR-BI and CD36 transfected cells Dr. Phillips also elucidated the role of SR-BI on free cholesterol efflux from cells. The results of these studies indicate that this receptor mediates free cholesterol (FC) efflux "independently of HDL tethering to the cell surface". SR-BI mediates a change on FC domains in plasma membrane that facilitate cholesterol flux.

Dr. G. Schmitz (University of Regensburg, Germany) further emphasized the importance of ABC1in the transport of cholesterol and phospholipids providing important details on its regulation. In macrophages cholesterol loading increases ABC1 mRNA and protein expression, reported Dr. Schmitz. In addition, ABC1 may play a role in inflammation. It is induced during monocyte to macrophage differentiation and may determine the tropism of monocyte for spleen or arterial wall, as documented by the mutations occurring in the ABC1 gene in Tangier disease (TD) and HDL deficiency, indicated Dr. Schmitz.

Aging may be an additional modulating factor of HDL cholesterol efflux, suggested Dr. K. Tsukamoto (University of Osaka, Japan). He reported that the reduction of efflux might be caused by an aging-mediated reduction of small G protein, a structure that may play an important role in cholesterol efflux.

The above-mentioned ability of cAMP to stimulate cholesterol efflux to apolipoproteins, could involve an increase in ABC1, as suggested by findings obtained by Dr. D. Wade (Univesity of Washington, U.S.A.). Treatment of RAW 264.7 macrophages with cAMP analogs increased ABC1 gene transcription in parallel with an increase of cholesterol efflux, illustrated Dr. Wade.

Finally, a different aspect of HDL protective role in atherogenesis was clarified by Dr. U. Panzenbock (University of Alberta, Canada). HDL may detoxify preformed pro-atherogenic lipid hydroperoxides still maintaining their antiatherosclerotic properties. The mild oxidation of apoA-I that may occur during this process does not counteract the beneficial effects of detoxification, specified Dr. Panzenbock.