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      The Link Between Human and Transgenic Animal Studies Involving Postprandial Hypertriglyceridemia and CETP Gene Polymorphisms

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          Abstract

          During last decades a considerable attempt has been made to prevent cardiovascular disease (CVD). Nevertheless, CVD remains a leading cause of death world wide [1]. The guidelines of medical scientific societies for primary and secondary prevention of CVD are directed towards established CVD risk factors (dyslipidemia, diabetes mellitus, hypertension, obesity, smoking and others). As far as dyslipidemia is concerned, the first priority, according to the guidelines [2], is to achieve optimal low density lipoprotein cholesterol (LDL-C) levels. Many clinical trials have shown that hypolipidemic treatment besides lowering LDL-C also significantly reduces CVD-related morbidity and mortality [3, 4]. Nevertheless, a considerable number of treated subjects still have CVD events. Thus, the need for additional therapeutic treatment such as increasing high density lipoprotein cholesterol (HDL-C) levels and decreasing levels of triglycerides (TG) has been suggested [5]. In this context, torcetrapib, an inhibitor of cholesteryl ester transport protein (CETP), increased HDL-C levels and decreased LDL-C levels [6-8]. However, the drug was withdrawn due to side effects. Another potential target to reduce CVD risk is postprandial hypertriglyceridemia [9, 10]. In 1979, Zilversmit [11] proposed that TG are involved in development of atherosclerosis. Since then, many research teams, including ours, [12-15] have examined the role of the exaggerated and delayed clearance of postprandial lipoprotein particles in various diseases [16, 17] including CVD. The mechanisms involved in postprandial lipemia were reviewed [18]. Considering all the above, the ideal gene associated with all 3 (TG, HDL and postprandial hypertriglyceridemia) is the one encoding for CETP. The mechanisms by which the CETP controls lipid metabolism have attracted many investigators, especially when plasma CETP concentration was found to be associated with the increased risk for premature atherosclerosis [19]. CETP activity depends on several factors such as environmental components (e.g. diet [20], alcohol consumption [21] and smoking [22]) gender [23] and genetic influence (e.g. polymorphisms of CETP) [24-26]. Few months ago, Salerno et al. examined the association between CETP and postprandial hypertriglyceridemia in transgenic mice [27]. They performed functional studies to show that plasma CETP activity modifies postprandial response of TG-rich lipoproteins. They assessed the TG response to fat load in rats with introduced human CETP gene (mice and rats are naturally CETP deficient). They found that elevated levels of CETP were associated with fat intolerance. Genetically, engineered mice have proven to be valid models for the study of CETP function and its relation with atherosclerosis. Introduction of the human CETP gene into mice results in a dose-related reduction of HDL-C levels and, as a consequence, these animals have significantly more early atherosclerotic lesions in the proximal aorta than control mice [28]. CETP variants have a strong impact on CETP activity and thus on HDL-C levels [29]. Several polymorphisms have been identified in the coding sequence of the CETP gene including I405V [30]. The I405V polymorphism has been associated with reduced CETP mass, increased HDL-C levels and increased CVD risk [31, 32]. Another widely studied CETP polymorphism is TaqIB which seems to influence HDL-C levels [33]. In normolipidemic subjects, the absence of the TaqIB restriction site (B2 allele) is associated with decreased CETP activity, increased HDL-C levels and reduced risk of CVD in males compared with B1 subjects [19]. The CETP TaqIB polymorphism has been found to account for 5.8% of the variance in HDL-C, which is important since the 1 mg/dl increase of HDL-C leads to 2% decrease in CVD risk [33, 34]. Subjects with the B2 allele usually have lower levels of CETP, higher levels of HDL-C and reduced risk of CHD compared with B1 subjects [33]. Our group also analyzed the association between TaqIB polymorphism and fasting as well as postprandial TG levels in heterozygote familial hypercholesterolemia (hFH) patients [35]. The B1 allele carriers with exaggerate TG response to fat loading had higher fasting and postprandial TGs compared with B2 allele carriers. Also, patients with the B1B2 genotype had significantly higher HDL-C levels compared with the B1B1 genotype. Noone et al. found that B1 allele carriers had increased mass and activity of CETP at 6 h after fat loading compared with B2 allele carriers [36]. This finding is similar to our results (higher TG 6 and 8 h after fat loading in B1 allele carriers compared with B2; p<0.05 and p<0.042, respectively). This was in accordance with other studies as well. Tall et al. found a 1.1–1.7-fold increase in CETP in response to a 135-g fat meal [37]. It has been shown by others [38, 39] and by us that carriers of the B1 allele have a more atherogenic fasting and non fasting lipid profile (low HDL-C, increased TGs, exaggerated and delayed clearance of TGs postprandially) than carriers of the B2 allele, which should lead to increased cardiovascular risk. Furthermore, Hogue et al. reported that a high plasma CETP concentration was associated with higher risk of having small-diameter particles of LDL in hFH patients, suggesting that CETP-induced remodeling of LDL is dependent on the number of TG-rich lipoproteins [40]. Also, in a previous study of ours [41] a significant gender association between TG response after oral fat loading and TaqIB polymorphism of the CETP gene in subjects with a exaggerate response was found. Specifically, men carrying the B2 allele of the TaqIB polymorphism showed a higher postprandial TG peak and a delayed return to baseline values compared with women carrying the B2 allele. The mechanisms of this observation were explained by Salerno et al. [27]. They reported that CETP expression in transgenic mice delays plasma clearance and liver uptake of TG-rich lipoproteins firstly, by transferring TGs to HDLs and increasing cholesteryl ester concentration of the remnant particles, and secondly by decreasing lipoprotein lipase (LPL) expression. Similarly, Zhou et al. [42] also found that adipocytes from adipose tissue of transgenic mice (CETP expressing) presented reduced LPL expression. The mechanisms underlying the differential lipemic responses confirmed in CETP expressing and non-expressing transgenic animals could also be applicable for humans expressing high or low CETP activities. Thus, the human studies performed by our group presented similar positive associations between CETP and TG levels [35]. Two other studies have also shown similar results [43, 44]. A new aspect linked to the effects of CETP expression contribute to a better understanding of the influence of a precise gene on lipids and lipoproteins responsiveness to nutritional fat. This research carried out in either humans or transgenic animals may have clinical implications in the near future. The understanding of postprandial lipemia is important, since postprandial hypertriglyceridemia is involved in endothelial dysfunction, oxidative stress, small dense LDL and small dense HDL particles [45].

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          Most cited references40

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          Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

          Drug therapy for hypercholesterolaemia has remained controversial mainly because of insufficient clinical trial evidence for improved survival. The present trial was designed to evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease (CHD). 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo. Over the 5.4 years median follow-up period, simvastatin produced mean changes in total cholesterol, low-density-lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%, and +8%, respectively, with few adverse effects. 256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0.66 (95% CI 0.59-0.75, p < 0.00001), and the respective probabilities of escaping such events were 70.5% and 79.6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularisation procedures. This study shows that long-term treatment with simvastatin is safe and improves survival in CHD patients.
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            Atherogenesis: a postprandial phenomenon.

            The hypothesis that plasma chylomicrons in persons who ingest a cholesterol-rich diet are atherogenic is evaluated. Evidence is presented that in humans, and experimental animals, chylomicron remnants as well as low-density lipoproteins are taken up by arterial cells. In persons who do not have familial hyperlipoproteinemia, atherogenesis may occur during the postprandial period. Research directions that may contribute to the evaluation of chylomicron remnants as a risk factor for atherogenesis are discussed. Lipoprotein studies after administration of a test meal containing fat and cholesterol are urgently needed.
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              Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.

              Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels. We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks. Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P<0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P<0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort. In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Open Cardiovasc Med J
                TOCMJ
                The Open Cardiovascular Medicine Journal
                Bentham Open
                1874-1924
                11 June 2009
                2009
                : 3
                : 48-50
                Affiliations
                [1 ]1 stCardiology Department, Onassis Cardiac Surgery Center Athens, Greece
                [2 ]Department of Clinical Biochemistry (Vascular Prevention Clinics), Royal Free campus, University College London Medical School, University College London London, UK
                Author notes
                [* ]Address correspondence to this author at the Onassis Cardiac Surgery Center, 356 Sygrou Ave 176 74 Athens, Greece; Tel: +30 210 9493520; Fax: +30 210 9493336; E-mail: genovefa@ 123456kolovou.com
                Article
                TOCMJ-3-48
                10.2174/1874192400903010048
                2701274
                19557147
                f8b931f2-f364-4f86-b9ed-ea072a53c08f
                © Kolovou et al.; Licensee Bentham Open.

                This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 15 May 2009
                : 18 May 2009
                : 20 May 2009
                Categories
                Article

                Cardiovascular Medicine
                Cardiovascular Medicine

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