November/December 2002

Lipid Education Service
Newsbrief

J. David Schnatz, M.D.

Recently, an inhibitor of CETP has been shown to raise HDL in humans (1). To deal with ineffective means of raising HDL and troubling side effects from medications such as nicotinic acid, a biotech firm, Avant Immunotherapeutics, has used a hybrid antigen to develop a vaccine to inhibit CETP (2). In rabbits, it raised HDL 42%. The company is said to be in Phase II clinical trials. What, then, is CETP? How does CETP correlate with HDL, and what is it's role in reverse cholesterol transport (RCT)? Is inhibition of CETP antiatherogenic?

What is CETP? CETP is a glycoprotein, composed of 476 amino acids (3). The major source is the liver. CETP is induced by high fat, high cholesterol diets. Exercise training programs reduce CETP while increasing HDL.

The role of CETP and other HDL binding proteins in RCT. RCT and the role of HDL and CETP in this process are well depicted and described (3). In RCT, HDL picks up cholesterol from peripheral tissues and transports it to the liver. During this process, lecithin cholesterol acyl transferase (LCAT) esterifies cholesterol to cholesterol ester (CE). A major role for CETP is to transfer CE from HDL to VLDL and LDL in exchange for triglyceride (TG). TG rich HDL is a byproduct. CE in VLDL and LDL can be taken up by the liver or returned to the periphery. Hepatic lipase converts TG rich HDL2 to TG poor HDL3 which returns to the RCT cycle. During this process, CE is released and taken up by the liver. HDL concentrations are a reflection of these processes which result in the total activity of the RCT pathway. Thus, as a general rule, increases in CETP lead to lowering of HDL cholesterol and vice versa.

Will inhibition of CETP be anti-atherogenic (3, 4, 5)? The issue is not clear-cut since some studies suggest that CETP is pro-atherogenic while others suggest that it is anti-atherogenic. Since CETP results in the transfer of cholesterol esters from HDL to VLDL and LDL, ie from anti-atherogenic to atherogenic particles, it seems to follow that CETP has an atherogenic effect, and decreasing CETP would be anti-atherogenic. On the other side of the equation, a further function of CETP is to transfer TG to HDL 2 particles, a substrate for hepatic lipase. A further function of CETP is the production of pre-beta 1 HDL from degradation of HDL 2. A reduction of these functions would tend to cause a back-up of the pathway and possible shunting of CE to the atherogenic apo B lipoprotein. Thus, it is not unreasonable to conclude that a reduction of CETP could be detrimental.

Evidence in favor of a pro atherogenic function of CETP, ie ., a low CETP is associated with a decreased risk of atherosclerosis and/or CHD.

Some species which lack CETP, such as mice, resist the harmful effects of a high cholesterol diet. Species with CETP, such as rabbits, monkeys and humans, are susceptible to the effects of a high cholesterol diet and increased atherosclerosis. Increased CETP activity correlates with increases in atherosclerosis in human dyslipidemia. Alcoholism is associated with a decrease in CETP, an increase in HDL and a decreased risk of atherosclerosis. Various mutations, many of which have been demonstrated in Japanese laboratories, showed that a reduced CETP correlates with an increased HDL and a decreased risk of atherosclerosis. Contrary mutations have been demonstrated and will be outlined in the next section. In one study, when CETP deficiency was associated with an HDL greater than 60 mg/dl, there was a low prevalence of atherosclerosis. When CETP deficiency existed without an increase in HDL, there was an increase in CHD. Analysis of the Framingham Offspring Studies has shown an association between genetic variation at the CETP Taq1B locus, HDL and CHD risk in men (6). Recent data from the Veteran's Administration HDL Intervention Trial (VA-HIT) has shown an association between the CETP Taq1B variant, HDL and CHD outcomes in men with CHD and low HDL (7).

Cholesterol fed rabbits develop atherosclerosis. Inhibition of CETP, chemically, produced an increase in HDL and a decrease in atherosclerosis compared to controls (4, 5). Short-term treatment of humans with CETP inhibitor was said to produce a 40-45% increase in HDL and a 15-20% decrease in LDL.

Inhibition of CETP in rabbits can be accomplished with antibodies to CETP or with oligodeoxynucleotides against CETP. In one study, this led to an increase in HDL and a marked decrease of aortic cholesterol content. Further, auto antibodies against CETP in rabbits, induced by vaccination, produced a decrease in CETP, an increase in HDL and significant reduction of aortic atherosclerotic lesions. Thus, "long-term inhibition of CETP is not only possible, but, in rabbits at least, reduced the susceptibility to atherosclerosis" (5).

Evidence of an anti-atherogenic function of CETP, ie., an increased CETP is associated with a decreased risk of atherosclerosis and/or CHD.

In Japanese/Hawaiian men, a mutation with CETP deficiency correlates with an increased risk of CHD (3). One study demonstrated a bimodal distribution of CETP in a group of individuals with a low HDL. A small number had an increase in CETP associated with a decreased incidence of CHD. The majority, however, had a normal CETP and an increased incidence of CHD (3).

Hyperalphalipoproteinemia is not always cardio protective (4). In an extensive analysis of lipoproteins in CETP deficiency, abnormal LDL and HDL lipoproteins were shown with the HDL having no preventive effect on cholesterol accumulation in mouse peritoneal macrophages. In a unique area in Japan with a high frequency of CETP mutations, a negative correlation of CHD and HDL was seen when the HDL was less than 70 mg/dl. When the HDL was greater than 70 mg/dl, the investigators saw an increased incidence of ischemia. Therefore, CETP deficiency was associated with an increase in atherogenesis and not increased longevity. Another study referenced in this article mentions a correlation between CETP deficiency and an increase in atherosclerotic plaques. "The above data seemed to show that CETP deficiency is atherogenic, but that atherogenecity in CETP deficiency is not always correlated with the level of plasma HDL-cholesterol" (4).

Summary of proatherogenesis vs antiatherogenesis. "Overall, studies of the Taq1B polymorphism have been consistent and supportive of a view that a lower level of CETP is associated with increased HDL cholesterol and (in men) a decreased risk of CHD. The results of studies of some other polymorphisms, however, support an opposite conclusion" (5). The conclusion from the VA-HIT analysis is, "the present data support the concept that increased HDL-C levels, resulting from reduced CETP activity, are beneficial with regard to CHD risk reduction and, furthermore, suggest that drugs aimed at HDL elevation via CETP inhibition are attractive candidates for CHD risk reduction in patients with HDL deficiency" (7).

The future for inhibition of CETP.

The evidence from genetic mutations is contradictory and much work needs to be done. However, it is clear that means to inhibit CETP are on the horizon, and that so far this has been associated with an increase in HDL. In rabbits, it has also been associated with a decrease in atherosclerosis. Time will tell whether or not such inhibition of CETP in humans will translate into a reduced cardiovascular risk.

References:

1. Circulation 105: 2159, 2002
2. Scientific American: February 2002, pages 32-33
3. Clinical Biochemistry 30: 517, 1997
4. Current Opinion in Lipidology 11: 589, 2000
5. Current Opinion in Lipidology 12: 377, 2001
6. Arterioscler Thromb Vasc Biol 20:1323, 2000
7. Arterioscler Thromb Vasc Biol 22:1448, 2002