POSIBLES PROBLEMAS

H D L has been thought to be directly protective via the mechanism o f reverse cholesterol transport (Tall 1990). Glomset (1968) suggested the involvement o f H D L in reverse cholesterol transport and coined this term. For convenience, reverse cholesterol transport, which is the transport of cholesterol from peripherial tissues back to the liver, is described in terms of three sequential stages, extravascular, intravascular and intraf\e^a(sc (Reichl & M iller 1986, 1989). The extravascular stage consists o f the transfer o f unesterified cholesterol from cells to cholesterol acceptors in interstitial fluid (reviewed in Reichl & Miller 1989). These cholesterol acceptors are small apoAI-containing particles called pre­ beta LpAI (Castro 1988) which are nascent HDLs, postulated to serve a key role in reverse

cholesterol transport (Fielding & Fielding 1980, Castro & Fielding 1988, Francone et al. 1989). Of all tissues, the arterial wall may depend most on reverse transport mediated by these small pre-beta LpAI (Reichl & Miller 1989), which are present at relatively high levels in human aortic intima and atherosclerotic lesions (Heideman & H off 1982, Castro et al.

1988).

The intravascular stage occurs in the plasma. The nascent HDLs [small spherical particles or apolipoprotein/phospholipid bilayer discs with pre-beta mobility (Tall 1990)] from the extravascular stage are rapidly modified by LCAT with apoAI as activator, into mature spherical HDL particles, rich in cholesteryl esters along the HDL^-» HDL3 -^HDLg-^HDLi cascade (Tall 1990, 1992). HDL enlargement occurs due to lipid influx and LCAT action (Deckelbaum et al. 1982, Tall 1990). The phospholipids and cholesterol in H D L act as substrates for LCAT, generating cholesteryl esters and lysolecithin which is bound to albumin or taken up by tissues (Tall 1992). The terminal intrahepatic phase consists o f delivery o f CE to heptacytes. The CE produced by the LCAT-catalysed reaction can undergo three fates (Tall 1992). Firstly CE can be transferred to TG-rich apoB-containing lipoproteins in a process involving cholesteryl ester transfer protein (CETP) and eventually taken up by heptacytes via receptor mediated catabolism o f CE-enriched apoB-containing remnant lipoproteins eg. IDL and LDL; this is the major pathway o f HDL C E catabolism in man (Tall 1992). Secondly, CE can be transferred directly into cells by selective non-particulate CE uptake, however its role in man remains speculative (Goldberg et al. 1991). Thirdly, CE can be catabolized with HDL particles; large HDL particles rich in apoE are taken up by receptor-dependent pathways (Mahley & Innerarity 1983).

There is a widespread, although still unsubstantiated, belief that these processes are antiatherogenic by virtue o f their potential to promote the efflux o f cholesterol from the artery wall (Barter 1993). However, it is not clear whether "reverse cholesterol transport" mediates the protective effect of H DL noted in epidemiological studies (Tall 1990). An inverse relationship between plasma HDL-C and tissue C stores, as measured by isotopic turnover studies, in humans was not found in a large group o f subjects (Blum et al. 1985) and the HDL deficiency states, Tangier disease, associated with accumulation o f CEs in tissue macrophages cmd hepatosplenomegaly (Breslow 1989) and LCAT deficiency do not

result in markedly increased atherosclerosis (Tall 1990).

T he alternative hypothesis is that low HDL is a marker for increased development of atherosclerosis via postprandial accumulation o f chylomicron or VLDL remnants (Patsch 1987, Tall 1990). Low levels o f HDL result from both inefficient lipolytic transfer of lipids into H D L and accelerated CE-TG interchange due to the accumulation o f TG-rich lipoproteins (Tall 1990). Postprandial lipaemia is strongly inversely correlated with HDL2 levels (Patsch et al. 1983) and postprandial enrichment o f HDLg with TGs is strongly postively associated with postprandial lipaemia (Patsch et al. 1984). It has long been known that patients with coronary heart disease exhibit an exaggerated postprandial triglyceride response after fat ingestion (eg. Moreton 1947, Angervall 1964), and recent case-control studies confirm this (Simpson et al. 1990, Groot et al. 1991, Patsch et al. 1992).

High levels o f postprandial TG-rich lipoproteins lead to enchanced CETP-mediated exchange with a shift o f cholesterol from HDL to atherogenic apoB-containing lipoproteins (Tall 1986). CETP, a plasma protein, mediates the heteroexchange o f CE in H D L for TGs in chylomicrons and VLDLs (Tall 1986). Accumulation o f CEs on VLDLs and LDLs decreases when levels of TG-rich lipoproteins are reduced with gemfibrozil in both fasting and postprandial states (Bhatnagar et al. 1992). Hayek et al. (1993) proved using transgenic mice, that CETP is a major mediator o f the well-known inverse relationship between TG and HDL-C (eg. Schaefer et al. 1978, Deckelbaum et al. 1984, Gordon et al. 1977) but that, in addition, this inverse relationship, on the background o f human apoAl, was still evident in the absence o f CETP, most apparent in animals with marked HTG, where HTG increased the fractional catabolic rate and decreased the transport rate o f HDL-CE. Recently Bhatnagar et al. (1993) demonstrated in-vitro an increased rate of accumulation o f CEs on VLDLs and LDLs in plasm a from patients with CAD compared to healthy controls with similar lipid levels, which could be due to increased free cholesterol content o f patients’ VLDLs - this has been demonstrated to accelerate the transfer of CEs from H D L to LDL and VLDL in hypercholesterolaemic plasma (Begdade et al. 1991) and patients with CAD have VLDLs enriched in free cholesterol (Mancini et al. 1988).

composition (Mann et al. 1991) may be more important than CETP activity in the transfer process. In man, the CETP pathway is o f major importance in HDL catabolism, influencing size, composition and quantity of HDL (Tall 1992), as illustrated by the altered lipoprotein profile in individuals with genetic CETP deficiency (Brown et al. 1989, Inazu et al. 1990, Koizumi et al. 1991). The lipoprotein profile in the absence o f CETP (ie. high HDL, high apoAI and low LDL) has low atherogenic potential, resembling that in animals (rats, pigs, dogs) lacking plasma CETP activity (Tall 1986) caused partly by greatly reduced catabolism o f both apoAI and apoAII (Ikewaki et al. 1993). On the other hand, transgenic mice expressing CETP had much worse atherosclerosis than did non-expressing controls, largely due to CETP-induced alterations in the lipoprotein profile (Marotti et al. 1993).