Human cholesteryl ester transfer protein measured by enzyme-linked immunosorbent assay with two monoclonal antibodies against rabbit cholesteryl ester transfer protein: plasma cholesteryl ester transfer protein and lipoproteins among Japanese hypercholesterolemic patients

Plasma cholesteryl ester transfer protein (CETP) concentrations were measured in Japanese subjects by an ELISA with two different monoclonal antibodies that were raised against rabbit CETP and cross-reacted against human CETP. Among 63 patients who consecutively underwent coronary angiography, the plasma CETP of 37 patients with luminal stenosis > or = 50% in their coronary arteries was not significantly different from that of the 26 patients with luminal stenosis < 50%. No other lipoprotein-related measurement except HDL-cholesterol differentiated the two groups. Among 40 hypercholesterolemic patients, no lipoprotein-related measurement other than LDL-cholesterol was found to positive correlate with the CETP. Before and after the treatment of 23 patients with simvastatin 5 mg a day for 4 weeks, plasma CETP markedly decreased in those whose pretreatment CETP was > or = 3 mg/L; no change was observed for those with lower pretreatment CETP. In the former group, negative correlation between CETP and HDL-cholesterol was demonstrated only in the posttreatment plasma.     

Dietary inulin lowers plasma cholesterol and triacylglycerol and alters biliary bile acid profile in hamsters

The mechanisms by which inulin may elicit its lipid-lowering effect are not well elucidated. To examine the lipid-lowering potential of inulin and especially its effect on bile acid metabolism, male golden Syrian hamsters were fed semipurified diets containing 20 g/100 g fat, 0.12 g/100 g cholesterol and 0 (control), 8, 12 or 16% inulin for 5 wk. Plasma total cholesterol concentrations were significantly lowered by 18, 15 and 29% in hamsters fed 8, 12 and 16% inulin, respectively. Dietary inulin specifically decreased VLDL cholesterol, which was significantly lower in hamsters fed 16% inulin compared with controls (1.1 +/- 0.3 vs. 2.9 +/- 0.6 mmol/L). LDL and HDL cholesterol were not significantly affected by dietary inulin. Plasma triacylglycerol was significantly reduced by 40 and 63% in hamsters fed 12 and 16% inulin, respectively. Hepatic total cholesterol and particularly esterified cholesterol accumulation were significantly lower in hamsters fed 8% inulin compared with controls. All three levels of dietary inulin caused distinct alterations in the bile acid profile of gallbladder bile. Taurochenodeoxycholic acid was significantly lower, whereas glycocholic and glycodeoxycholic acid were greater in hamsters fed inulin. Daily fecal bile acid excretion (micromol/d) tended to be greater (P = 0.056) in inulin-fed hamsters compared with controls, whereas daily neutral sterol excretion was not affected. These data demonstrate that the lipid-lowering action of inulin is possibly due to several mechanisms, including altered hepatic triacylglycerol synthesis and VLDL secretion and impaired reabsorption of circulating bile acids.     

Plasma cholesteryl ester transfer protein activity in hyper- and hypothyroidism

Thyroid dysfunction is associated with multiple changes in lipoprotein metabolism, and we have determined the effects of thyroid dysfunction on plasma cholesteryl ester transfer protein (CETP) activity. CETP is a plasma protein that mediates the exchange of cholesteryl ester and triglyceride between plasma lipoproteins and plays an important role in high-density lipoprotein metabolism and in the reverse cholesterol transport pathway. Plasma CETP activity was assayed in 18 hyperthyroid and in 17 hypothyroid patients, before and after treatment, by measuring the transfer of cholesteryl esters from exogenous radiolabeled high-density lipoprotein to apolipoprotein B-containing lipoproteins. Plasma CETP activity was increased in hyperthyroid patients, compared with their matched controls (22.11 +/- 8.92% transferred/5 microL.4 h vs. 16.75 +/- 6.48, P < 0.05), whereas in hypothyroid patients, plasma CETP activity was decreased (11.14 +/- 4.84% transferred/5 microL.4 h vs. 17.26 +/- 7.13, P < 0.01). Plasma CETP activity decreased after treatment of thyrotoxicosis, although a significant change was observed, mainly in the severely thyrotoxic patients with free T4 > 100 pmol/L (n = 11, 25.61 +/- 8.12% transferred/5 microL.4 h vs. 21.71 +/- 7.84, P < 0.05). In the hypothyroid patients, there was a significant increase in plasma CETP activity after thyroxine replacement (11.14 +/- 4.84% transferred/5 microL.4 h vs. 15.46 +/- 6.71, P < 0.01). There was a strong positive correlation between log(free T4) and plasma CETP activity (r = 0.51, P < 0.001). In summary, both hyper- and hypothyroidism are associated with significant changes in plasma CETP activity, and these changes are corrected when the patients have been rendered euthyroid.     

Suppression of plasma cholesteryl ester transfer protein activity in acute hyperinsulinemia and effect of plasma nonesterified fatty acid

Cholesteryl ester transfer protein (CETP) is a major determinant of the plasma high-density lipoprotein cholesterol (HDL-C) level and plays an important role in the reverse cholesterol transport system. The purpose of this study was to determine the effect of acute hyperinsulinemia on plasma CETP activity in normal subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). Hyperinsulinemia was achieved using the hyperinsulinemic-euglycemic clamp. CETP activity was determined as the transfer of radiolabeled cholesterol in HDL3 to acceptor lipoprotein. Mean plasma CETP activity during an insulin infusion in both subject groups was significantly decreased compared with the mean basal activity. Suppression of plasma CETP activity in the NIDDM patients was significantly less than in the normal subjects (-4.2% +/- 7.9% v -9.6% +/- 6.4%, P < .02). Regression analysis showed that this suppression was correlated with plasma nonesterified fatty acid (NEFA) levels after the clamp and with the magnitude of the NEFA decrease (r = .318, P < .02 and r = .292, P < .05, respectively). The data suggest that acute hyperinsulinemia reduces plasma CETP activity through a decrease in plasma NEFA.     

Cholesteryl ester transfer protein activity enhances plasma cholesteryl ester formation. Studies in CETP transgenic mice and human genetic CETP deficiency

The plasma cholesteryl ester transfer protein (CETP) promotes the removal of HDL cholesteryl esters and is thought to stimulate reverse cholesterol transport (RCT). However, mechanisms by which CETP may stimulate RCT are poorly understood. Thus, we examined the relationship between plasma CETP expression and plasma cholesteryl ester formation in CETP transgenic (Tg) mice, hamsters, and human subjects with genetic CETP deficiency. Incubation of CETP Tg mouse plasma showed a 20% to 40% increase in plasma cholesterol esterification rate (CER, P < .05) compared with control mice. Injection of a neutralizing CETP monoclonal antibody (MAb) (TP2) into natural flanking region CETP Tg mice resulted in an increase in plasma free cholesterol (FC) concentration, FC/CE ratio, FC/phosphatidylcholine ratio, and hepatic CETP mRNA. In hamsters, CETP inhibition also resulted in an increase in plasma FC/phosphatidylcholine ratio and increased CETP mRNA in adipose tissue. In humans with two common CETP gene mutations (an intron 14 splicing defect and a D442G missense mutation), mean plasma CERs were 39 and 60, respectively, compared with 89 nmol x mL-1 x h-1 in normal subjects. By contrast, lecithin:cholesterol acyltransferase (LCAT) mass was normal in CETP-deficient subjects. MAb neutralization of CETP activity in incubated human plasma did not alter the LCAT reaction, even after supplementation with discoidal HDL and VLDL. Thus, genetic alterations in CETP levels lead to secondary changes in the plasma LCAT reaction, possibly because of remodeling of HDL by CETP acting in concert with other factors in vivo. In human genetic CETP deficiency, a moderate impairment in the plasma LCAT reaction may contribute to a defect in RCT, providing a potential mechanism to explain the recently observed excess of coronary heart disease in these subjects.     

Streptozotocin- and alloxan-induced diabetes modifies total plasma and lipoprotein lipid concentration and composition without altering cholesteryl ester transfer activity

Although educators in clinical settings assume different roles, the major responsibilities are the clinical and professional development of staff. Some of the challenges facing educators relate to maintaining expertise, maintaining visibility, and managing work load. In this article, the authors describe the responsibilities of the educator and the challenges and strategies for success in the clinical educator role.     

Relationship between lipoprotein lipase and high density lipoprotein cholesterol in mice: modulation by cholesteryl ester transfer protein and dietary status

Plasma lipoprotein lipase (LPL) activity correlates with high density lipoprotein (HDL) cholesterol levels in humans. However, in several mouse models created either through transgenesis or targeted inactivation of LPL, no significant changes in HDL cholesterol values have been evident. One possible explanation for this species difference could be the absence of plasma cholesteryl ester transfer protein (CETP) activity in mice. To explore this possibility and further investigate interactions between LPL and CETP modulating HDL cholesterol levels in vivo, we examined the relationship between LPL activity and HDL levels in mice expressing the simian CETP transgene, compared with littermates not carrying the CETP gene. On a chow diet, increasing LPL activity was associated with a trend towards increased HDL levels (51 +/- 29 vs. 31 +/- 4 mg/dL highest vs. lowest tertiles of LPL activity, P = 0.07) in mice expressing CETP, while no such effects were seen in the absence of CETP (65 +/- 12 vs. 61 +/- 15 mg/ dL). Furthermore, in the presence of CETP, a significant positive correlation between LPL activity and HDL cholesterol was evident (r = 0.15, P = 0.006), while in the absence of CETP no such correlation was detected (r = 0.15, P = 0.36), highlighting the interactions between LPL and CETP in vivo. When mice were challenged with a high fat, high carbohydrate diet, strong correlations between LPL activity and HDL cholesterol were seen in both the presence (r = 0.45, P = 0.03) and absence (r = 0.73, P < 0.001) of CETP. Therefore, under altered metabolic contexts, such as those induced by dietary challenge, the relation between LPL activity and HDL cholesterol may also become evident. Here we have shown that both genetic and environmental factors may modulate the association between LPL activity and HDL cholesterol, and provide explanations for the absence of any changes in HDL values in mice either transgenic or with targeted disruption of the LPL gene.     

Cholesteryl ester transfer protein mutations, protein activity and HDL-cholesterol concentration

Three diffuse centroblastic lymphomas developed at the site of previous surgery. Two were preceded by atypical lymphoid infiltrates. Clinical data, microscopic features, and immunophenotypic studies were reviewed. All three patients presented with soft tissue masses at the site of previous surgery and metallic implants, with no evidence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. There was no history of immunosuppression or risk factors. In two cases the initial diagnosis was of atypical lymphoid infiltrate progressing to lymphoma. Pathological examination showed a diffuse centroblastic lymphoma with an angiocentric pattern in one case. Phenotypic studies confirmed B cell origin. Soft tissue malignant lymphoma, though uncommon, can occur at the site of previous orthopaedic surgery, in particular joint replacement. Atypical lymphoid infiltrate may signal such an event.     

Reduced cholesteryl ester transfer in plasma of patients with lipoprotein lipase deficiency

The net mass transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to the apolipoprotein (apo) B-containing lipoproteins, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) in plasma (cholesteryl ester transfer (CET)) from three patients lacking lipoprotein lipase (LpL) activity was significantly lower (P < 0.001) than in plasma from fasting control subjects with comparable triglyceride levels. Chylomicrons isolated from LpL-deficient fasting plasma showed the same low level of CET activity as observed in the intact plasma when combined with HDL and cholesteryl ester transfer protein (CETP)-containing d 1.063 g/ml bottom fractions from control subjects. Preincubation of chylomicrons and large triglyceride-rich lipoproteins (Sf > 400) from LpL-deficient plasma with milk LpL, however, stimulated the capacity to engage in CET 4- to 5-fold to the same level as chylomicrons and VLDL from control subjects after a fat load. Consistent with these measurements of CET activity in plasma, chylomicrons obtained from the LpL-deficient subjects after a 14-h fast had higher TG/CE ratios than chylomicrons from controls 3 h after ingesting a fat load (LpL-deficient 26.3 +/- 9.0 vs. controls 6.9 +/- 2.1; mean +/- SD). The mass of CETP did not differ in LpL-deficient and control subjects (LpL-deficient 1.03 +/- 0.22 micrograms/ml vs. controls 1.58 +/- 0.58 micrograms/ml). These studies are consistent with earlier in vitro studies showing that the actions of lipoprotein lipase and its lipolytic products are essential, for maximal cholesteryl ester transfer protein activity.     

Effect of enduracin on the activity of a cholesterol ester transfer protein in blood plasma of people with hypercholesteremia

Dr. Ellen R. Wiebe's study of the use of methotrexate and misoprostol in combination for early termination of intrauterine pregnancy (see pages 165 to 170 of this issue) is the first Canadian study of the use of this drug combination for medical abortion. The authors compare Wiebe's findings with those of earlier studies on methotrexate and misoprostol, as well as with European findings on the use of mifepristone with prostaglandins. The authors argue that although the methotrexate-misoprostol combination appears to be reasonably safe for the woman, the failure rate and the teratogenicity of methotrexate and misoprosol give cause for concern. The authors conclude that medical abortions ought to be offered only where there is adequate access to laboratory and surgical facilities and where losses to follow-up are systematically minimized to reduce the potential for continued pregnancy resulting in congenital abnormality.     

Opposite effects of cholesteryl ester transfer protein and phospholipid transfer protein on the size distribution of plasma high density lipoproteins. Physiological relevance in alcoholic patients

The aim of the present study was to investigate the role of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) in determining the size distribution of high density lipoproteins (HDL) in human plasma. Whereas both purified CETP and PLTP preparations were able to promote the size redistribution of isolated HDL3, CETP favored the emergence of small HDL, while PLTP induced the formation of both small and large conversion products. When the total plasma lipoprotein fractions isolated from nine distinct subjects were incubated for 24 h at 37 degrees C with either purified PLTP or purified CETP, significant alterations in the relative proportions of the five distinct plasma HDL subpopulations, i.e., HDL2b (9.71-12.90 nm), HDL2a (8.77-9.71 nm), HDL3a (8.17-8.77 nm), HDL3b (7.76-8.17 nm), and HDL3c (7.21-7. 76 nm) were also observed. PLTP induced a significant increase in the relative abundance of HDL2b (8.66 +/- 2.34% versus 7.87 +/- 1. 83% in controls; p < 0.01) and a significant decrease in the relative abundance of HDL3a (32.76 +/- 3.42% versus 37.87 +/- 2.62% in controls; p < 0.05). In contrast, CETP significantly reduced the relative proportion of HDL2a (33.03 +/- 2.53% versus 37.56 +/- 6.43% in controls; p < 0.01) but significantly increased the relative proportion of both HDL3b (21.36 +/- 6.97% versus 15.58 +/- 7.75% in controls; p < 0.01) and HDL3c (3.21 +/- 4.84% versus 1.13 +/- 0.56% in controls; p < 0.05). Finally, in order to assess further the physiological relevance of in vitro observations, CETP activity, PLTP activity, and HDL size distribution were determined in plasmas from 33 alcoholic patients entering a cessation program. Alcohol withdrawal was associated with (i) a significant increase in plasma CETP activity (173.5 +/- 70.5%/h/ml before versus 223.2 +/- 69. 3%/h/ml after alcohol withdrawal, p = 0.0007), (ii) a significant reduction in plasma PLTP activity (473.9 +/- 203.7%/h/ml before versus 312.7 +/- 148.4%/h/ml after alcohol withdrawal, p = 0.0001), and (iii) a significant shift of large HDL2b and HDL2a toward small HDL3b and HDL3c. On the one hand, changes in plasma CETP activity correlated negatively with changes in the proportion of HDL2a (r = -0.597, p = 0.0002) and positively with changes in the proportion of HDL3b (r = 0.457, p = 0.0075). On the other hand, changes in plasma PLTP activity correlated positively with changes in the proportion of HDL2b (r = 0.482, p = 0.0045) and negatively with changes in the proportion of HDL3a (r = -0.418, p = 0.0154). Taken together, data of the present study revealed that plasma PLTP and CETP can exert opposite effects on the size distribution of plasma HDL. PLTP can promote the formation of HDL2b particles at the expense of HDL3a, while CETP can promote the formation of HDL3b particles at the expense of HDL2a.     

Elevated high density lipoprotein concentrations in heart transplant recipients are related to impaired plasma cholesteryl ester transfer and hepatic lipase activity

Accelerated atherosclerosis is a major complication of heart transplantation, and is frequently associated with a dyslipoproteinemia characterized by a paradoxical increase in HDL-cholesterol concentration. To define this abnormality, the lipoprotein profiles of 25 heart transplant recipients (HTR) were analyzed and compared with those of 26 control subjects. HDL, as separated on the basis of density in 3 subfractions, were increased in concentration: HDL2: +51%, HDL3a: +29%, HDL3b: +32%. HDL2 and HDL3a displayed an enrichment in surface components, phospholipids, unesterified cholesterol and apo E, leading to an increased size compared with subfractions of similar density in the controls. The major steps of plasma HDL metabolism were investigated: cholesterol esterification (LCAT activity), cholesteryl ester transfer to apo B-containing lipoproteins (CETP) and the hepatic hydrolysis of HDL components (HL activity). We demonstrated a partial deficiency in CETP (-28%) and hepatic lipase (-36%) activities with normal LCAT activity. Correlations in total study population (HTR plus controls) evidenced negative associations between CETP activity and HDL3a concentrations and between HL activity and HDL2-cholesterol as a percent of total HDL-cholesterol. Therapeutic agents used in post transplantation treatment such as glucocorticoids and/or cyclosporine may be speculated thus to affect both CETP and HL activities and, by arresting the HDL cycle in a CE-saturated state, do decrease the efficiency of reverse cholesterol extraction at the site of the graft.     

Influence of plasma cholesteryl ester transfer activity on the LDL and HDL distribution profiles in normolipidemic subjects

The relations of cholesteryl ester transfer protein (CETP) activity to the distribution of low density lipoproteins (LDLs) and high density lipoproteins (HDLs) were investigated in fasting plasma samples from 27 normolipidemic subjects. LDL and HDL subfractions were separated by electrophoresis on 20-160 g/L and 40-300 g/L polyacrylamide gradient gels, respectively. Subjects were subdivided into two groups according to their LDL pattern. Monodisperse patterns were characterized by the presence of a single LDL band, whereas polydisperse patterns were characterized by the presence of several LDL bands of different sizes. To investigate the influence of lipid transfers on LDL patterns, total plasma was incubated at 37 degrees C in the absence of lecithin:cholesterol acyltransferase (LCAT) activity. The incubation induced a progressive transformation of polydisperse patterns into monodisperse patterns. Under the same conditions, initially monodisperse patterns remained unchanged. Measurements of the rate of radiolabeled cholesteryl esters transferred from HDL3s to very low density lipoproteins (VLDLs) and LDLs revealed that subjects with a monodisperse LDL pattern presented a significantly higher plasma CETP activity than subjects with a polydisperse LDL pattern (301 +/- 85%/hr per milliliter versus 216 +/- 47%/hr per milliliter, respectively; p < 0.02). In addition, when total plasma was incubated for 24 hours at 37 degrees C in the absence of LCAT activity, the relative mass of cholesteryl esters transferred from HDLs to apolipoprotein B-containing lipoproteins was greater in plasma with monodisperse LDL than in plasma with polydisperse LDL (0.23 +/- 0.06 versus 0.17 +/- 0.06, respectively; p < 0.02). These results indicated that in normolipidemic plasma, CETP could play an important role in determining the size distribution of LDL particles. The analysis of lipoprotein cholesterol distribution in the two groups of subjects sustained this hypothesis. Indeed, HDL cholesterol levels, the HDL:VLDL+LDL cholesterol ratio, and the esterified cholesterol:triglyceride ratio in HDL were significantly lower in plasma with the monodisperse LDL pattern than in plasma with the polydisperse LDL pattern (p < 0.01, p < 0.01, and p < 0.02, respectively). Plasma LCAT activity did not differ in the two groups. Plasma CETP activity correlated positively with the level of HDL3b (r = 0.542, p < 0.01) in the entire study population. Whereas plasma LCAT activity correlated negatively with the level of HDL2b (r = -0.455, p < 0.05) and positively with the levels of HDL2a (r = 0.475, p < 0.05) and HDL3a (r = 0.485, p < 0.05), no significant relation was observed with the level of HDL3b.(ABSTRACT TRUNCATED AT 400 WORDS)     

Apolipoprotein A-I metabolism in cholesteryl ester transfer protein transgenic mice. Insights into the mechanisms responsible for low plasma high density lipoprotein levels

Expression of simian cholesteryl ester transfer protein (CETP) in C57BL/6 mice causes the animals' high density lipoprotein (HDL) levels to decrease. The purpose of these studies was to determine how CETP expression caused that reduction. Chemical analysis showed that the HDL of the CETP transgenic mice had about twice as much triglyceride and only about 60% as much cholesteryl ester as the HDL from the C57BL/6 mice. Both strains of mouse had high levels of a circulating lipase. When plasma from the mice was incubated at 37 degrees C for 5 h, the triglycerides in the HDL were hydrolyzed, and apoA-I was shed from the particle. However, apoA-I was shed from the CETP HDL more rapidly than it was shed from the C57BL/6 HDL. Because "free" apoA-I is rapidly cleared by the kidney, increased production of free apoA-I would be expected to shorten the average life span of apoA-I in the mouse. Kinetic analyses indicated that the life span of apoA-I was significantly reduced in the CETP transgenic mice. It was concluded that CETP expression enriched the core of the HDL with triglyceride, which rendered it vulnerable to lipolysis, causing apoA-I to be shed from the particle. That shortened the life span of apoA-I in the CETP mice, which led to lower plasma levels of the protein.     

Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100 000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL2-CE (r = -0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL2-CE remained unchanged. Postprandial HDL3 of controls were enriched with phospholipid (PL) (30.3 +/- 2.6% at 6 h) with respect to fasting (25.6 +/- 2.5%, P < 0.01) and to NIDDM-HDL3 (25.8 +/- 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL2-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL3 with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL3 enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.     

Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene

The human cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins. The activity of CETP results in a reduction in HDL cholesterol levels, but CETP may also promote reverse cholesterol transport. Thus, the net impact of CETP expression on atherogenesis is uncertain. The influence of hypertriglyceridemia and CETP on the development of atherosclerotic lesions in the proximal aorta was assessed by feeding transgenic mice a high cholesterol diet for 16 wk. 13 out of 14 (93%) hypertriglyceridemic human apo CIII (HuCIII) transgenic (Tg) mice developed atherosclerotic lesions, compared to 18 out of 29 (62%) controls. In HuCIII/CETPTg, human apo AI/CIIITg and HuAI/CIII/CETPTg mice, 7 of 13 (54%), 5 of 10 (50%), and 5 of 13 (38%), respectively, developed lesions in the proximal aorta (P < .05 compared to HuCIIITg). The average number of aortic lesions per mouse in HuCIIITg and controls was 3.4 +/- 0.8 and 2.7 +/- 0.6, respectively in HuCIII/CETPTg, HuAI/CIIIg, and HuAI/CIII/CETPTg mice the number of lesions was significantly lower than in HuCIIITg and control mice: 0.9 +/- 0.4, 1.5 +/- 0.5, and 0.9 +/- 0.4, respectively. There were parallel reductions in mean lesion area. In a separate study, we found an increased susceptibility to dietary atherosclerosis in nonhypertriglyceridemic CETP transgenic mice compared to controls. We conclude that CETP expression inhibits the development of early atherosclerotic lesions but only in hypertriglyceridemic mice.     

Role of female sex steroids in regulating cholesteryl ester transfer protein in transgenic mice

The role of sex steroids in the regulation of cholesteryl ester transfer protein (CETP) was examined in the following groups of female transgenic mice carrying the human CETP gene: (1) normal, (2) ovariectomized, (3) ovariectomized and treated with estrogen; (4) ovariectomized and treated with progesterone; (5) ovariectomized and treated with both hormones, and (6) ovariectomized and treated with tamoxifen. CETP activity was measured in the plasma, and in the particulate and the soluble fractions of liver, muscle, and adipose tissue. Human CETP specific activity was determined by taking the difference of cholesterol ester transfer in the presence and absence of an antibody (TP2) against human CETP Ovariectomy reduced hormone levels, but did not completely abolish them from the circulation. Plasma CETP activity was significantly reduced in the tamoxifen group. There were significant reductions in CETP in liver homogenate and the soluble fraction, as well as in the particulate fraction of adipose with ovariectomy. Hormone replacement did not restore CETP activity in either the plasma or the tissues. Tamoxifin treatment resulted in a decrease in CETP activity in both fractions of liver, but had no effect on adipose. In the soluble fraction of adipose tissue and both fractions of muscle, only trace CETP activity was detected. We conclude that (1) minimal amounts of sex steroid hormones may be sufficient to affect CETP expression; (2) the effects of sex steroid hormones vary among tissues; and (3) in addition to the sex steroids, factor(s) from the ovary are needed for the full expression of CETP in this animal model.