(2); however, the precise effects of CETP on atherogenesis are controversial. In humans, increased incidence of coronary heart disease has been associated with both CETP deficiency (3) and augmentation (4). In several animal models of atherosclerosis, the effects of CETP on vascular health are clearly dependent upon the metabolic context (5-11).Various researchers are attempting to target CETP as a form of therapy (9-13), but these approaches will be useless unless the circumstances where CETP acts as pro-or anti-atherogenic are properly clarified.Deficiency in endogenous estrogen accounts for the loss of protection against coronary heart disease after menopause or following bilateral ovariectomy (14). Estrogen deficiency per se does not alter plasma CETP activity as shown in castrated CETP transgenic mice (15). Also, estrogen therapy has no impact on the plasma CETP activity in humans (16) as well as in apolipoprotein B/CETP double transgenic mouse model (17).The present study aimed at investigating whether CETP expression would alter the development of atherosclerosis in a moderately hypercholesterolemic mouse model lacking ovarian hormones. For this purpose, mice expressing the human CETP gene were crossbred with LDL receptor (LDLR) knockout mice. On a high fat diet, the LDLR knockout mice develop extensive aorta atherosclerosis in a pattern similar to humans (18,19). We have shown here that the expression of the CETP gene significantly reduced the development of atherosclerotic lesions in ovariectomized hypercholesterolemic mice. Furthermore, this antiatherogenic effect of CETP was blunted by the estrogen replacement therapy.

In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism and dietinduced 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 nTg mice), whereas the HDL fraction was reduced (230% for CETP and 211% 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. Gender differences in coronary artery disease (CAD) risk observed during the reproductive life period have been attributed to an attenuating effect of estrogen on atherogenesis (1, 2) and/or to a proatherogenic action of androgens (3, 4). However, the unexpected outcomes from the Women's Health Initiative and Heart and Estrogen Replacement Study trials (5, 6) and other controversies about the role of androgens (7) necessitate further investigation of the role of sex steroids, especially in sexmatched individuals. Androgen's effects on lipoprotein metabolism and risk of atherosclerosis are not unequivocal (7,8). Increased endogenous serum testosterone in men has been associated with a favorable lipid profile (9, 10), and low endogenous levels of testosterone have been associated with an atherogenic lipid profile (11, 12) and CAD (13,14). However, other studies have not found such relationships (15-18). Aromatization of testosterone into 17b-estradiol seems to be an important determinant of the beneficial effects of androgens observed in men (19,20) and mice (21,22). On the other hand, increasing endogenous androgen levels in women (23, 24), androgenic supplementation in men (3), in women (25), and in female animals (26,27), and nonmedical use of androgenic anabolic steroids (4,28,29) are associated with increased risk factors for atherosclerotic diseases.Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) from HDL to apolipoprotein B-containing lipoproteins (apoB-LPs) in exchange for triglycerides (TGs), thus remodeling HDL composition in the plasma of sev...

Our purpose was to determine the blood amino acid concentration during insulin induced hypoglycemia (IIH) and examine if the administration of alanine or glutamine could help glycemia recovery in fasted rats. IIH was obtained by an intraperitoneal injection of regular insulin (1.0 U/kg). The blood levels of the majority of amino acids, including alanine and glutamine were decreased (P < 0.05) during IIH and this change correlates well with the duration than the intensity of hypoglycemia. On the other hand, the oral and intraperitoneal administration of alanine (100 mg/kg) or glutamine (100 mg/kg) accelerates glucose recovery. This effect was partly at least consequence of the increased capacity of the livers from IIH group to produce glucose from alanine and glutamine. It was concluded that the blood amino acids availability during IIH, particularly alanine and glutamine, play a pivotal role in recovery from hypoglycemia.

The CETP (cholesteryl ester transfer protein) is a plasma protein synthesized in several tissues, mainly in the liver; CETP reduces plasma HDL (high-density lipoprotein) cholesterol and increases the risk of atherosclerosis. The effect of CETP levels on postprandial intravascular metabolism of TAGs (triacylglycerols) is an often-overlooked aspect of the relationship between CETP and lipoprotein metabolism. Here, we tested the hypothesis that CETP delays the plasma clearance of TAG-rich lipoprotein by comparing human CETP expressing Tg (transgenic) and non-Tg mice. After an oral fat load, the postprandial triglyceridaemia curve was markedly increased in CETP-Tg compared with non-Tg mice (280+/-30 versus 190+/-20 mg/dl per 6 h respectively, P<0.02). No differences in intestinal fat absorption and VLDL (very-low-density lipoprotein) secretion rates were observed. Kinetic studies of double-labelled chylomicron-like EMs (emulsions) showed that both [(3)H]triolein and [(14)C]cholesteryl oleate FCRs (fractional clearance rates) were significantly reduced ( approximately 20%) in CETP-Tg mice. Furthermore, TAG from lipid EM pre-incubated with CETP-Tg plasma had plasma clearance and liver uptake significantly lower than the non-Tg plasma-treated lipid EM. In addition, reductions in post-heparin plasma LPL (lipoprotein lipase) activity (50%) and adipose tissue mRNA abundance (39%) were verified in CETP-Tg mice. Therefore we conclude that CETP expression in Tg mice delays plasma clearance and liver uptake of TAG-rich lipoproteins by two mechanisms: (i) transferring TAG to HDLs and increasing CE content of the remnant particles and (ii) by diminishing LPL expression. These findings show that the level of CETP expression can influence the responsiveness to dietary fat and may lead to fat intolerance.

No abstract