The Yin and Yang of cholesteryl ester transfer protein and atherosclerosis.

Of late, there has been a major renewal of interest into the protective effect of high-density lipoprotein (HDL)cholesterol on atherogenesis and coronary disease [1,2]. This derives from the ability of HDL to transport cholesterol from peripheral tissue back to the liver [i.e. reverse cholesterol transport (RCT)] and from specific anti-atherogenic properties of HDL, including antioxidant, antithrombotic and anti-inflammatory effects [3,4]. Fundamental to understanding the in vivo metabolism of HDL and its role in atherosclerosis is cholesteryl ester transfer protein (CETP) [5,6]. CETP is a plasma glycoprotein that mediates the transfer and exchange of neutral lipids (cholesteryl esters and triacylglycerol [triglyceride]) between HDL (specifically HDL # ) and apolipoprotein (apo)-B-containing lipoproteins. Because of the relative lipid content of these lipoproteins, the net effect of CETP is to transfer cholesteryl esters from HDL to very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL), and triacylglycerols from VLDL to HDL and LDL. CETP thus contributes to RCT by channelling cholesterol from extra-hepatic tissue to apoB-containing lipoproteins that are subsequently catabolized in the liver, the other route for RCT being via the classical HDL pathway. Moreover, in concert with the enzyme hepatic lipase, CETP converts HDL # particles into HDL $ and apoAI, thus generating the molecular initiators of cellular cholesterol efflux. Great intrigue has surrounded all these functions of CETP, with disparate sources of evidence suggesting that CETP may be both proand anti-atherogenic. Genetic deficiency in CETP, due to missense and nonsense mutations, results in increased plasma levels of HDL-cholesterol in humans. In the Honolulu Heart Study [7], Japanese-American men with a common genetic deficiency in CETP (due to an Asp%%#Gly substitution in exon 15) had moderate increases in HDLcholesterol to 1.5 mmol}l and a 50% increased risk of coronary heart disease (CHD), in contrast with a decreased risk in those whose HDL-cholesterol was greater than 1.5 mmol}l. In hypertriglyceridaemic individuals in this population, a low CETP genotype, due to an Ile%!&Val mutation, was also associated with increased CHD risk. Combined CETP and hepatic triacylglycerol lipase deficiency was also associated with increased risk of atherosclerosis [8], again possibly due to co-existent hypertriglyceridaemia. Conflicting evidence has also been provided in European studies [9,10], with certain restriction fragment length polymorphisms of the human CETP gene resulting in high plasma HDL-cholesterol concentrations in association with a paradoxical increase in CHD risk in women. Studies in transgenic mice have also challenged the anti-atherogenic status of CETP. Mice are naturally deficient in CETP, and when atherosclerosis is induced with cholesterol feeding or with apoE or LDL-receptor knockouts, insertion of a simian CETP transgene accelerates progression of atherosclerosis [11,12]. In contrast, in mice overexpressing human apoCIII, the CETP transgene appears to be anti-atherogenic [13]. Hence, in this animal model, it appears that CETP is proatherogenic in the setting of increased concentration of LDL-cholesterol or remnants, but anti-atherogenic in the presence of hypertriglyceridaemia, due to accumulation of VLDL. In contrast with mice, rabbits have naturally high plasma levels of CETP. Experiments in cholesterol-fed rabbits have consistently shown that decreased expression of CETP using antisense oligodeoxynucleotides against CETP [14], or inhibition of CETP activity using anti-CETP antibodies [15], increases the plasma concentrations of HDL-cholesterol and results in a marked reduction in aortic cholesterol content. Despite the controversies surrounding the role of CETP in atherosclerosis, several pharmacological inhibitors of CETP activity have been developed for potential therapeutic use. A promising compound is JTT-705. This is a thioester that forms disulphide bonds with CETP and when taken orally can inhibit CETP activity in rabbits by 95%. An earlier study by Okamoto et al. [16] showed that oral administration of 255 mg}kg JTT-705 to rabbits with diet-induced hypercholesterolaemia increased HDL-cholesterol by 90%, decreased non-HDL-cholesterol by 40% and, after 6 months, decreased atherosclerotic lesions by 80%. The study reported by Inazu et al. [17] in this issue of Clinical Science aimed to extend these promising earlier observations by examining the dose-dependent effects of JTT-705 on aortic atherosclerosis in rabbits with a more severe degree of hypercholesterolaemia. Using similar experimental methods, an apparently well-powered study and an appropriate interventional design, the authors found no effect of JTT-705 at low (100 mg}kg) or high (300 mg}kg) doses on aortic cholesterol content in cholesterol-fed Japanese white rabbits. This occurred in spite of a significant increase in HDL-cholesterol by 200% and up to 70% inhibition of CETP activity. These results need to be interpreted on the basis that the experimental diet used induced a much higher level of plasma cholesterol of 14.3 mmol}l compared with