CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion

The aim of this work was to study how CETP expression affects whole body cholesterol homeostasis. Thus, tissue uptake and plasma removal rates of labeled HDL-cholesteryl ester (CE), VLDL secretion rates, and biliary lipid secretion and fecal bile acid content were compared between human CETP transgenic (Tg) and non-transgenic (nTg) mice fed with a standard diet. CETPTg mice exhibited increased HDL-CE plasma fractional catabolic rate and uptake by the liver, adrenalls, adipose tissue and spleen. HDL fractions from both CETP Tg and from nTg mice were removed faster from the plasma of CETP expressing than from nTg mice, suggesting a direct role of CETP in accelerating tissue CE uptake. However, neither hepatic output of VLDL cholesterol and triglycerides nor biliary lipid and fecal bile acid excretion were changed in CETP Tg compared to nTg mice. CETP Tg mice also showed enhanced hepatic cholesterol content. Steady state cholesterol homeostasis was probably preserved through the downregulation of hepatic HMG-CoA reductase and LDL receptor expression. In conclusion, although CETP expression facilitates cholesteryl ester tissue uptake, it does not alter biliary lipid and fecal bile acid excretion, the mandatory final step of the reverse cholesterol transport. (c) 2006 Elsevier Ireland Ltd. All rights reserved.191231331

Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice

Reduced estrogen levels result in loss of protection from coronary heart disease in postmenopausal women. Enhanced and diminished atherosclerosis have been associated with plasma levels of cholesteryl ester transfer protein (CETP); however, little is known about the role of CETP-ovarian hormone interactions in atherogenesis. We assessed the severity of diet-induced atherosclerosis in ovariectomized (OV) CETP transgenic mice crossbred with LDL receptor knockout mice. Compared with OV CETP expressing ((+)), OV CETP non-expressing ((-)) mice had higher plasma levels of total, VLDr-, LDL-, and HDL-cholesterol, as well as higher antibodies titers against oxidized LDL. The mean aortic lesion area was 2-fold larger in OV CETP- than in OV CETP+ mice (147 +/- 90 vs. 73 +/- 42 x 10(3) mum(2), respectively). Estrogen therapy in OV mice blunted the CETP dependent differences in plasma lipoproteins, oxLDL antibodies, and atherosclerosis severity. Macrophages from OV CETP+ mice took up less labeled cholesteryl ether (CEt) from acetyl-LDL than macrophages from OV CETP- mice. Estrogen replacement induced a further reduction in CEt uptake and an elevation in HDL mediated cholesterol efflux from pre-loaded OV CETP+ as compared with OV CETP- macrophages. These findings support the proposed anti-atherogenic role of CETP in specific metabolic settings.441334

Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice

In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism anddietinduced atherosclerosis. CETP transgenic mice and nontransgenic (nTg) littermates were studied 4 weeks after bilateral orchidectomy or sham operation. Castrated mice had an increase in the LDL fraction (136% for CETP and 179% for nTgmice), whereas the HDL fraction was reduced (230% for CETP and -11% for nTg mice). Castrated mice presented 1.7-fold higher titers of anti-oxidized LDL (Ox-LDL) antibodies than sham-operated controls. Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration. Kinetic studies showed no differences in VLDL secretion rate, VLDL-LDL conversion rate, or number of LDL and HDL receptors. Competition experiments showed lower affinity of LDL from castrated mice for tissue receptors. Diet-induced atherosclerosis studies showed that testosterone deficiency increased by 100%, and CETP expression reduced by 44%, the size of aortic lesion area in castrated mice. In summary, testosterone deficiency increased plasma levels of apolipoprotein B-containing lipoproteins (apoB-LPs) and anti-OxLDL antibodies, decreased LDL receptor affinity, and doubled the size of diet-induced atherosclerotic lesions. The expression of CETP led to a milder increase of apoB-LPs and reduced atherosclerotic lesion size in testosterone-deficient mice.4771526153

Oxidation of LDL enhances the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer rate to HDL, bringing on a diminished net transfer of cholesteryl ester from HDL to oxidized LDL

Cholesteryl ester transfer protein (CETP) plays a controversial role in atherogenesis by contributing to the net transfer of high density lipoprotein (HDL) cholesteryl ester (CE) to the liver via apolipoprotein-B-containing lipoproteins (apoB-LP). We evaluated in vitro the CETP-mediated bidirectional transfer of CE from HDL to the chemically modified pro-atherogenic low density lipoprotein (LDL) particles. Acetylated or oxidized (ox) LDL. either unlabeled or [H-3]-CE labeled. were incubated with [C-14]-CE-HDL in the presence of the lipoprotein-deficient plasma fraction (d>1.21 g/ml) as the source of CETP. The amount of radioactive CE transferred was determined after dextran sulfate/MgCl2, precipitation of LDL. The results showed a 1.4-2.8-fold lower HDL-CE transfer to acetylated LDL while no effect was: observed on the CE transfer to oxidized LDL. However. the reverse transfer rate of [H-3]CE-LDL to HDL was 1.4-3.6 times greater when LDL was oxidized than when it was intact. Overall, HDL, was better than HDL, as donor of CE to native LDL. probably reflecting the relatively greater CE content of HDL2. Oxidation of LDL enhanced the CETP-mediated cholesteryl ester transfer rate to HDL, bringing on a reduced net transfer rate of cholesteryl ester from HDL to ox LDL. This may diminish the oxLDL particle's atherogenic effect. (C) 2001 Elsevier Science B.V. All rights reserved.304416719910

Plasma 27-hydroxycholesterol/cholesterol ratio is increased in low high density lipoprotein-cholesterol healthy subjects

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Sterol 27-hydroxylase converts cholesterol to 27-hydroxycholesterol (27-OHC) which is widely distributed among tissues and is expressed at high levels in the vascular endothelium and macrophages. There is a continuous flow of this oxysterol from the tissues into the liver; where it is converted to bile acids. Objective: Measure plasma concentrations of 27-OHC in subjects that differ according to their plasma HDL-C concentration. Methods: Healthy men presenting low HDL-C (1.55 mmol/L), n 18, BMI <30 kg/m(2) were recruited after excluding secondary causes that might interfere with their plasma lipid concentrations such as smoking, heavy drinking and diabetes. Blood samples were drawn after a 12 h fasting period for the measurement of 27-OHC by the combined GC/MS analysis utilizing deuterium-label internal standards. Results: The plasma ratio 27-OHC/total cholesterol (median and range nmoL/mmoL) was 50.41 (27.47-116.00) in the High HDL-C subjects and 6334 (36.46-91.18) in the Low HDL-C subjects (p = 0.0258). Conclusion: Our data indicate that the production of 27-0HC by extrahepatic tissues and its transport to the liver may represent an alternative pathway for a deficient reverse cholesterol transport system when plasma HDL-C is low. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.461516191621Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)LIMHC/FMUSP (Medical Investigation Laboratories, Hospital das Clinicas/Faculty of Medical Sciences of University of Sao Paulo)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2010/52654-6

Cholesteryl ester transfer protein and lipid metabolism and cardiovascular diseases

In this chapter, we present the major advances in CETP research since the detection, isolation, and characterization of its activity in the plasma of humans and several species. Since CETP is a major modulator of HDL plasma levels, the clinical importance of CETP activity was recognized very early. We describe the participation of CETP in reverse cholesterol transport, conflicting results in animal and human genetic studies, possible new functions of CETP, and the results of the main clinical trials on CETP inhibition. Despite major setbacks in clinical trials, the hypothesis that CETP inhibitors are anti-atherogenic in humans is still being tested.12761525CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP300937/2018-02017/17728-8; 2015/17555-0; 2013/07607-