2.4. Reverse cholesterol transport

2.4.1. HDL

HDL is responsible for most of the reverse cholesterol transport in man, as it is the only particle capable of receiving cholesterol from the peripheral cells (Funke 1997).

2.4.2. Apolipoprotein A1

Apolipoprotein A1 is the major lipoprotein in HDL and the primary acceptor for unesterified cholesterol from the peripheral tissues (von Eckardstein et al. 1993, Forte et al. 1993). The plasma apo A1 concentration is lower in smokers than in non-smokers (Dullaart et al. 1994), and exercise training increases the plasma level of apo A1 (Foger et al. 1994). Simvastatin has been reported to increase the plasma apo A1 concentration, especially in patients with nonfamilial hyperlipoproteinemia type II a (Homma et al. 1995). Several epidemiological studies have revealed an inverse relationship between coronary artery disease and the plasma apo A1 concentration (Stampfer et al. 1991, Buring et al. 1992, Amouyel et al. 1993).

2.4.3. Cholesteryl ester transfer protein

The cholesteryl ester transfer protein (CETP) is a glycoprotein synthesised mainly in the liver, but also in the intestine, spleen and adrenal glands. In plasma, CETP is predominantly bound to HDL containing apo-A1-only particles (Bruce et al. 1995). CETP mediates the exchange of HDL cholesteryl esters with triglycerides of apo B containing lipoproteins, and it plays a central role in the reverse cholesterol transport from the peripheral tissues to the liver (Bruce & Tall 1995). CETP gene expression is upregulated in response to increased dietary cholesterol or endogenous hypercholesterolemia (Tall 1995), and its concentration is elevated in hyperlipidemia (Lagrost et al. 1995). CETP plasma levels correlate with total cholesterol, VLDL cholesterol and apo E concentrations (McPherson et al. 1991), and its activity correlates with elevated LDL cholesterol and reduced HDL cholesterol in type IIa and IIb hypercholesterolemia (Tato et al. 1995a). Dietary correction of the lipoprotein changes results in a reduction of the plasma CETP concentration and an increase in HDL cholesterol in chylomicronemia and dysbetalipoproteinemia (McPherson et al. 1991). Alcohol consumption reduces the plasma CETP activity and concentration (Hannuksela et al. 1992). Genetic deficiency of CETP is associated with elevated HDL cholesterol and apolipoprotein (apo) A1 and decreased LDL cholesterol and apo B (Sakai et al. 1995).

It has been suggested that the increase in CETP associated with hypercholesterolemia is secondary to the elevation of serum cholesterol rather than its cause (Bruce & Tall 1995). CETP activity is higher in smokers than in non-smokers (Dullaart et al. 1991, Freeman et al. 1993), and short-term exercise training reduces CETP mass and activity (Seip et al. 1993, Foger et al. 1994). However, endurance athletes have higher CETP activity than controls (Gupta et al. 1993), and females have higher CETP levels than males (Marcel et al. 1990), and the prevalence of coronary heart disease is lower in males with low HDL and high CETP activity compared to men with low HDL and normal CETP activity (Tato et al. 1995b), suggesting that although CETP reduces the HDL levels, it seems to have a dominantly anti-atherogenic action in vivo (Tall 1995).

2.4.4. Apolipoprotein E

The apo E phenotype can modify the reverse cholesterol transport in several mechanisms. Plasma of individuals with apo E 3 is capable of receiving more cholesterol from fibroblasts than plasma of individuals homozygous for E2 or E4 (Huang et al. 1995). Apo E enhances the cholesteryl ester and triglyceride exchange between VLDL and HDL, possibly by enhancing the affinity of CETP for VLDL (Kinoshita et al. 1993). The apo E genotype influences the plasma CETP and HDL cholesterol responses to dietary cholesterol. Normocholesterolemic males with the genotype E 2/3 showed no change in HDL cholesterol, but had an increase of 37% in the CETP response after cholesterol feeding, the respective changes for apo E 3/3 being +4% and +18% and for apo E 4/3 +12% and +9% (Martin et al. 1993).