Biomedical subjects

Andre Theriault

Publications and source records attributed to Andre Theriault.

6 recordsLinked to original sources

PubMed2003

Human serum albumin and its structural variants mediate cholesterol efflux from cultured endothelial cells.

In the present study, we used the human EA.hy926 endothelial cell line as the model system to investigate the effect of human serum albumin (HSA) and its structural variants on cholesterol efflux. Initial studies showed that HSA promoted cholesterol efflux in a dose- and time-dependent manner, reaching a plateau at 10 mg/ml at 90 min. As a control, gelatin displayed no significant effect on efflux, while HSA was significantly more efficient than ovalbumin and bovine serum albumin (BSA) in promoting cholesterol efflux. Equal molar concentrations of HSA and apolipoprotein A-I (apoA-I) showed that apoA-I had considerably higher efficiency in efflux. However, the prevailing high plasma concentrations of HSA may compensate for its lower efflux rate compared to apoA-I. To characterize the mechanism of HSA-mediated cholesterol efflux, we studied the effects of cAMP and temperature on efflux using both EA.hy926 endothelial cells and murine RAW 264.7 macrophages. We found that HSA-mediated efflux occurred via a cAMP-independent and relatively temperature-insensitive pathway. We next examined the nature of HSA-cholesterol interaction by comparing the effects of various HSA mutants to wild-type HSA on cholesterol efflux. We found specific interactions between subdomains 2A and 3A and cholesterol, as indicated by the changes in the efflux rate of various HSA mutants. In conclusion, our study provides evidence for the role of HSA in cholesterol efflux, and shows that the substitution of specific amino acid residues in subdomains of 2A and 3A may be important structural determinants in its ability to bind to cholesterol and participate in cholesterol efflux.

Apolipoprotein A-I↗

PubMed2003

Emergence of the metabolic syndrome in childhood: an epidemiological overview and mechanistic link to dyslipidemia.

Insulin resistance and type 2 diabetes are rapidly emerging as major disorders of childhood and adolescence. This appears to be closely linked to a rapid rise in the prevalence of obesity in the pediatric population. The development of insulin resistance appears to lead to a "metabolic syndrome" which includes a number of major complications such as dyslipidemia and hypertension. Childhood metabolic syndrome promotes the development of premature atherosclerosis and significantly increases cardiovascular disease risk early in life. The mechanisms linking obesity, insulin resistance, and metabolic dyslipidemia are not fully understood. This review will attempt to discuss some of the key mechanistic issues surrounding insulin resistance and its association with metabolic dyslipidemia. Most of the recent progress in this field has come from the use of genetic and diet-induced animal models of insulin resistance. New data from these animal studies particularly the fructose-fed hamster, a model of metabolic syndrome and dyslipidemia, will be reviewed. Evidence from both animal and human studies suggest a key role for insulin sensitive tissues such as adipose tissue, liver, and intestine in the development of an insulin resistant state and its associated lipid and lipoprotein disorders. The critical interaction of metabolic signals among these tissues appears to govern the transition from an insulin sensitive to an insulin resistant state that underlies dyslipidemic conditions.

Animals↗

PubMed2002

Intestinal apolipoprotein B secretion is inhibited by the flavonoid quercetin: potential role of microsomal triglyceride transfer protein and diacylglycerol acyltransferase.

Recent studies have yielded evidence that plant flavonoids reduce hepatic lipid and apolipoprotein B (apoB) secretion. However, the possible role of flavonoids in regulating lipid and apoB secretion by the intestine has not been studied. The purpose of our study was to examine the effects of quercetin, a common dietary flavonoid, on TAG and apoB secretion in a human intestinal cell-line, CaCo-2. Differentiated postconfluent CaCo-2 cells grown on filters and pretreated with quercetin for 8 h were shown by ELISA to inhibit basolateral apoB secretion in a dose-dependent manner. At 15 microM, the secretion of both apoB-100 and apoB-48 were inhibited similarly. This effect was shown to be specific, as quercetin did not affect the incorporation of [35S]methionine/cysteine into secreted TCA-precipitable proteins. To determine the mechanism underlying this inhibitory effect, we examined two regulatory points: TAG availability and lipid transfer to the lipoprotein particle. Quercetin inhibited TAG synthesis under both basal and lipid-rich conditions, indicating that lipid availability is a determining factor in the regulation of apoB secretion by quercetin. The reduction was due at least in part to a decrease in diacylglycerol acyltransferase activity. We next examined lipid transfer or lipidation of the lipoprotein particle by analyzing microsomal TAG transfer protein (MTP) activity. Quercetin decreased MTP activity moderately. In summary, the data demonstrated that pharmacological concentrations of quercetin are a potent inhibitor of intestinal apoB secretion and that reduced lipid availability and lipidation in the lipoprotein assembly step are the mechanism for the suppression of apoB-containing lipoprotein secretion by quercetin in CaCo-2 cells.

Acyltransferases↗

PubMed2002

Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes.

Alpha-tocopherol and its esterified derivatives have been shown to be effective in reducing monocytic-endothelial cell adhesion. However, the effect of alpha-tocotrienol (alpha-T3) has not been characterized. In the present study, using human umbilical vein endothelial cells (HUVEC) as the model system, we examined the relative inhibitory effects of alpha-T3 and other vitamin E derivatives on cell surface adhesion molecule expression under TNF-alpha stimulation. Using enzyme-linked immunosorbent assay, we demonstrated that alpha-T3 markedly inhibited the surface expression of vascular cell adhesion molecule-1 in TNF-alpha activated HUVEC in a dose- and time-dependent manner. The optimal inhibition was observed at 25 micromol/l alpha-T3 within 24 h (77+/-5%) without cytotoxicity. In addition, the surface expression of intercellular adhesion molecule-1 and E-selectin were also reduced by 40+/-7 and 42+/-5%, respectively. In order to further evaluate the effects of alpha-T3 on the vascular endothelium, we investigated the ability of monocytes to adhere to endothelial cells. Interestingly, a 63+/-3% decrease in monocytic cell adherence was observed. Compared to alpha-tocopherol and alpha-tocopheryl succinate, alpha-T3 displayed a more profound inhibitory effect on adhesion molecule expression and monocytic cell adherence. This inhibitory action by alpha-T3 on TNF-alpha-induced monocyte adhesion was shown to be NF-kappaB dependent and was interestingly reversed with co-incubation with farnesol and geranylgeraniol, suggesting a role for prenylated proteins in the regulation of adhesion molecule expression. In summary, the above results suggest that alpha-T3 is a potent and effective agent in the reduction of cellular adhesion molecule expression and monocytic cell adherence.

Antioxidants↗

PubMed2002

Green tea catechins decrease apolipoprotein B-100 secretion from HepG2 cells.

To understand the hypocholesterolemic activity of green tea, our in vitro studies screened the relative efficacy of two structurally distinct green tea catechins, epicatechin (EC) and epigallocatechin gallate (EGCG), on apolipoprotein B-100 (apoB) and lipid production using a well established human hepatoma cell-line, HepG2, as the model system. This study showed that HepG2 cells pretreated with EC and EGCG for 8 h exerted a dose-dependent inhibitory effect on apoB secretion. Total protein and albumin synthesis and secretion were unaffected indicating the effects on apoB secretion to be specific. Under lipid-rich conditions, apoB secretion was markedly reduced by EGCG and to a lesser extent by EC at 50 microM. Mechanistic study showed that tea catechins inhibited apoB secretion via a proteasome-independent pathway as indicated by a lack of response to N-acetyl-leucyl-leucyl-norleucinal (ALLN), a proteasome inhibitor. The effect on apoB secretion was also found to be independent of lipid biosynthesis. In summary, the data suggest that EGCG in contrast to EC is a potent inhibitor of apoB secretion. The results indicate that the gallate moiety in the catechin molecule may result in a beneficial effect on lipid metabolism in terms of apoB secretion.

Anticholesteremic Agents↗

PubMed2002

Inhibitory effect of delta-tocotrienol, a HMG CoA reductase inhibitor, on monocyte-endothelial cell adhesion.

We have previously shown that alpha-tocotrienol (alpha-T3), a vitamin E analogue and HMG CoA reductase (HMGR) inhibitor, markedly inhibited monocyte-endothelial cell adhesion, a process that was reversed with the addition of mevalonate intermediates involved in protein prenylation. Since delta-T3 and gamma-T3 possess greater HMGR inhibition than alpha-T3, we postulated that these analogues might have a greater effect on protein prenylation, and thus on monocyte adhesion and endothelial adhesion molecule expression in comparison to alpha-T3. Hence, we pursued to investigate the effect of various analogues of tocotrienol (alpha, gamma, delta) on monocytic cell adhesion and expression of adhesion molecules using a human umbilical vein endothelial cell-line, EA.hy926, as the model system. Relative to alpha-T3, delta-T3 displayed a more profound inhibitory effect on monocytic cell adherence using a 15 micromol/L concentration within 24 h (delta: 42 +/- 5%; alpha: 26 +/- 8% vs. control). This inhibitory action was reversed by co-incubation with farnesol and geranylgeraniol, suggesting a role for prenylated proteins in the regulation of monocyte adhesion. To further evaluate the effect of tocotrienols on the vascular endothelium, we measured the surface expression of adhesion molecules. Compared to alpha-T3, delta-T3 markedly inhibited the expression of VCAM-1 (delta: 57 +/- 6%; alpha: 37 +/- 10% vs. control) and E-selection (delta: 36 +/- 3%; alpha: 18 +/- 6% vs. control) in TNF-alpha activated endothelial cells. The above result suggests that delta-T3 is a potent and effective agent for the reduction of cellular adhesion molecule expression and monocytic cell adherence.

Arteriosclerosis↗