Wiedendiol-A inhibits cholesteryl ester binding to its transfer protein.
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AIM: To study the wiedendiol-A (W-A) inhibition mechanism of plasma cholesteryl ester (CE) transfer protein (CETP) on the transfer of CE. METHODS: Using gel filtration method. RESULTS: W-A at 30 mumol.L-1 inhibited association of CE with CETP by 76% and CETP transfer activity by 81%. In addition, W-A enhanced binding of TP2, a monoclonal antibody with a CETP C-terminal epitope which is involved in CE binding, to CETP, suggesting a W-A-induced conformational change at the epitope for increased TP2 binding. When CETP activity was measured by varying high-density lipoproteins (HDL) concentration, the apparent Vmax of CE transfer was inhibited by 74% and 83% in the presence of W-A at 14 and 25 mumol.L-1, respectively, while the apparent K(m) of HDL for CETP did not change. CONCLUSION: W-A action is mediated through interaction between W-A and CETP, but not through those between W-A and lipoproteins. (+info)
Effect of 14 weeks of resistance training on lipid profile and body fat percentage in premenopausal women.
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OBJECTIVES: To study the effects of a supervised, intensive (85% of one repetition maximum (1-RM)) 14 week resistance training programme on lipid profile and body fat percentage in healthy, sedentary, premenopausal women. SUBJECTS: Twenty four women (mean (SD) age 27 (7) years) took part in the study. Subjects were randomly assigned to either a non-exercising control group or a resistance exercise training group. The resistance exercise training group took part in supervised 45-50 minute resistance training sessions (85% of 1-RM), three days a week on non-consecutive days for 14 weeks. The control group did not take part in any structured physical activity. RESULTS: Two way analysis of variance with repeated measures showed significant (p < 0.05) increases in strength (1-RM) in the exercising group. There were significant (p < 0.05) decreases in total cholesterol (mean (SE) 4.68 (0.31) v 4.26 (0.23) mmol/1 (180 (12) v 164 (9) mg/dl)), low density lipoprotein (LDL) cholesterol (2.99 (0.29) v 2.57 (0.21) mmol/l (115 (11) v 99 (8) mg/dl), the total to high density lipoprotein (HDL) cholesterol ratio (4.2 (0.42) v 3.6 (0.42)), and body fat percentage (27.9 (2.09) v 26.5 (2.15)), as well as a strong trend towards a significant decrease in the LDL to HDL cholesterol ratio (p = 0.057) in the resistance exercise training group compared with their baseline values. No differences were seen in triglycerides and HDL cholesterol. No changes were found in any of the measured variables in the control group. CONCLUSIONS: These findings suggest that resistance training has a favourable effect on lipid profile and body fat percentage in healthy, sedentary, premenopausal women. (+info)
Kinetics of hemin distribution in plasma reveals its role in lipoprotein oxidation.
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Hemin is a powerful in vitro inducer of low-density lipoprotein (LDL) oxidation, implicated in development of atherosclerosis. To support the proposed role of hemin in atherogenesis, the question of whether hemin has any chance of getting together with LDL in vivo, must be addressed. A stopped-flow technique was employed in order to investigate the fast kinetics of hemin binding to LDL and to other plasma hemin-binding proteins: high-density lipoprotein (HDL), albumin and hemopexin. Based on the measured rate constants of hemin association with and dissociation from each of these proteins, time-dependent hemin distribution in plasma was analyzed. The analysis shows that as much as 80% of total hemin binds initially to LDL and HDL, the plasma components which are most susceptible to oxidation. Only then hemin partially transfers to the antioxidants albumin and hemopexin. The half time of the hemin-LDL complex in plasma, initially comprising 27% of total hemin, was more than 20 s. Not only transient, but also oxidatively active steady-state hemin-lipoprotein complexes in plasma were both predicted from the kinetic analysis and found in experiment. Our data suggest that the hemin-LDL complex may exist in vivo and that its oxidative potential should be considered pro-atherogenic. (+info)
Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure.
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BACKGROUND: Chronic renal failure (CRF) is associated with hypertriglyceridaemia and depressed plasma high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I (Apo A-I) concentrations. Uraemic hypertriglyceridaemia is due, in part, to lipoprotein lipase and hepatic lipase deficiencies, which are causally linked to excess parathormone (PTH). This study was designed to test the hypothesis that depressed plasma concentration and abnormal composition of HDL in CRF may be due to dysregulation of hepatic expression of Apo A-I and/or the newly discovered HDL receptor. METHODS: Hepatic Apo A-I and HDL receptor mRNA abundance (Northern blot), and HDL receptor protein mass (Western blot) were determined in CRF rats (5/6 nephrectomy), parathyroidectomized CRF rats (CRF-PTx) and sham-operated controls. RESULTS: The CRF group exhibited normal hepatic HDL receptor mRNA and HDL receptor protein abundance coupled with reduced hepatic Apo A-I mRNA. Hepatic Apo A-I mRNA, HDL receptor mRNA and protein abundance were not affected by PTx. CONCLUSIONS: CRF results in the down-regulation of hepatic Apo A-I gene expression, which accounts for the known reduction in plasma Apo A-I concentration. However, CRF does not affect HDL receptor mRNA or protein expression in this model. Neither Apo A-I nor HDL receptor expression were modified by PTx in CRF rats. (+info)
Hypochlorite modification of high density lipoprotein: effects on cholesterol efflux from J774 macrophages.
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The present study was aimed at investigating effects of hypochlorite (HOCl) modification of high density lipoproteins subclass 3 (HDL3) on their ability for cellular cholesterol removal from permanent J774 macrophages. Our findings indicate that HOCl (added as reagent or generated enzymatically by the myeloperoxidase/H2O2/Cl- system) damages apolipoprotein A-I, the major protein component of HDL3. Fatty acid analysis of native and HOCl-modified HDL3 revealed that unsaturated fatty acids in both major lipid subclasses (phospholipids and cholesteryl esters) are targets for HOCl attack. HOCl modification resulted in impaired HDL3-mediated cholesterol efflux from J774 cells, regardless of whether reagent or enzymatically generated HOCl was used to modify the lipoprotein. Decreased cholesterol efflux was also observed after HOCl modification of reconstituted HDL particles. Impairment of cholesterol efflux from macrophages was noticed at low and physiologically occurring HOCl concentrations. (+info)
Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I.
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The transport of HDL cholesteryl esters (CE) from plasma to the liver involves a direct uptake pathway, mediated by hepatic scavenger receptor B-I (SR-BI), and an indirect pathway, involving the exchange of HDL CE for triglycerides (TG) of TG-rich lipoproteins by cholesteryl ester transfer protein (CETP). We carried out HDL CE turnover studies in mice expressing human CETP and/or human lecithin:cholesterol acyltransferase (LCAT) transgenes on a background of human apoA-I expression. The fractional clearance of HDL CE by the liver was delayed by LCAT transgene, while the CETP transgene increased it. However, there was no incremental transfer of HDL CE radioactivity to the TG-rich lipoprotein fraction in mice expressing CETP, suggesting increased direct removal of HDL CE in the liver. To evaluate the possibility that this might be mediated by SR-BI, HDL isolated from plasma of the different groups of transgenic mice was incubated with SR-BI transfected or control CHO cells. HDL isolated from mice expressing CETP showed a 2- to 4-fold increase in SR-BI-mediated HDL CE uptake, compared to HDL from mice lacking CETP. The addition of pure CETP to HDL in cell culture did not lead to increased selective uptake of HDL CE by cells. However, when human HDL was enriched with TG by incubation with TG-rich lipoproteins in the presence of CETP, then treated with hepatic lipase, there was a significant enhancement of HDL CE uptake. Thus, the remodeling of human HDL by CETP, involving CE;-TG interchange, followed by the action of hepatic lipase (HL), leads to the enhanced uptake of HDL CE by cellular SR-BI. These observations suggest that in animals such as humans in which both the selective uptake and CETP pathways are active, the two pathways could operate in a synergistic fashion to enhance reverse cholesterol transport. (+info)
Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females.
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The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food low-fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDL-C. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C. (+info)
Hepatic lipase promotes the selective uptake of high density lipoprotein-cholesteryl esters via the scavenger receptor B1.
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Hepatic lipase (HL) plays a major role in high-density lipoprotein (HDL) metabolism both as a lipolytic enzyme and as a ligand. To investigate whether HL enhances the uptake of HDL-cholesteryl ester (CE) via the newly described scavenger receptor BI (SR-BI), we measured the effects of expressing HL and SR-BI on HDL-cell association as well as uptake of 125I-labeled apoA-I and [3H]CE-HDL, by embryonal kidney 293 cells. As expected, HDL cell association and CE selective uptake were increased in SR-BI transfected cells by 2- and 4-fold, respectively, compared to controls (P < 0.001). Cells transfected with HL alone or in combination with SR-BI expressed similar amounts of HL, 20% of which was bound to cell surface proteoglycans. HL alone increased HDL cell association by 2-fold but had no effect on HDL-CE uptake in 293 cells. However, in cells expressing SR-BI, HL further enhanced the selective uptake of CE from HDL by 3-fold (P < 0.001). To determine whether the lipolytic and/or ligand function of HL are required in this process, we generated a catalytically inactive form of HL (HL-145G). Cells co-transfected with HL-145G and SR-BI increased their HDL cell association and HDL-CE selective uptake by 1.4-fold compared to cells expressing SR-BI only (P < 0.03). Heparin abolished the effect of HL-145G on SR-BI-mediated HDL-CE selective uptake.Thus, the enhanced uptake of HDL-CE by HL is mediated by both its ligand role, which requires interaction with proteoglycans, and by lipolysis with subsequent HDL particle remodeling. These results establish HL as a major modulator of SR-BI mediated selective uptake of HDL-CE. (+info)