Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.

Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/ oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.

Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects.

BACKGROUND: We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects. METHODS: We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-1HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption. RESULTS: In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-1HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities. CONCLUSIONS: These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis.

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample. METHODS: The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography. RESULTS: No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 - 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed. CONCLUSIONS: None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.

Impact of high cholesterol intake on tissue cholesterol content and lipid transfers to high-density lipoprotein.

OBJECTIVE: Esterified cholesterol is the storage form of cholesterol in the organism. High-density lipoprotein (HDL), where free cholesterol is transferred from other lipoproteins and tissues, is the main esterification site in plasma. The aim of this study was to investigate how high cholesterol intake changes free/esterified ratios of cholesterol in the plasma, aorta, liver and lipid transfers to HDL. METHODS: Twenty male Golden Syrian hamsters fed 0.5% cholesterol for 15 wk and 19 controls without cholesterol feeding were sacrificed to determine serum lipids, transfer proteins (cholesteryl ester transfer protein and phospholipid transfer protein), and amount of free and esterified cholesterol in the aorta and liver. In vitro transfer of radioactive free and esterified cholesterol, phospholipids, and triacylglycerols to HDL was performed by incubating whole plasma with an artificial nanoemulsion used as a lipid donor and measuring radioactivity in the HDL fraction after chemical precipitation of non-HDL fractions and of the nanoemulsion. RESULTS: Compared with controls, cholesterol-fed animals showed a 137% increase in non-HDL plasma fraction and a 61% increase in HDL (P < 0.001). The esterified/free cholesterol ratio in non-HDL and HDL fractions did not change. In the aorta, free cholesterol increased 55% and the esterified/free ratio (0.2) decreased. Cholesterol accumulation in the liver was several-fold greater and esterified/free increased (1.3). Cholesterol feeding pronouncedly increased the transfer of free and esterified cholesterol, phospholipids, and triacylglycerols to HDL and cholesteryl ester transfer protein and phospholipid transfer protein activities. CONCLUSIONS: Free cholesterol is cytotoxic and less stable than esterified cholesterol, and the present data on how the organism responds to high cholesterol intake with respect to esterified/free ratios in the plasma, aorta, liver, and lipid transfers to HDL may have physiopathologic implications.

Lipid transfer proteins: past, present and perspectives.

Lipid transfer proteins (PLTP and CETP) play roles in atherogenesis by modifying the arterial intima cholesterol content via altering the concentration and function of plasma lipoproteins and influencing inflammation. In this regard, endotoxins impair the reverse cholesterol transport (RCT) system in an endotoxemic rodent model, supporting a pro-inflammatory role of HDL reported in chronic diseases where atherosclerosis is premature. High PLTP activity related to atherosclerosis in some clinical studies, but the mechanisms involved could not be ascertained. In experimental animals the relation of elevated plasma PLTP concentration with atherosclerosis was confounded by HDL-C lowering and by unfavorable effects on several inflammatory markers. Coincidently, PLTP also increases in human experimental endotoxemia and in clinical sepsis. Human population investigations seem to favor low CETP as atheroprotective; this is supported by animal models where overexpression of huCETP is atherogenic, most likely due to increased concentration of apoB-lipoprotein-cholesterol. Thus, in spite of CETP facilitating the HDL-C-mediated RCT, the reduction of apoB-LP-cholesterol concentration is the probable antiatherogenic mechanism of CETP inhibition. On the other hand, experimental huCETP expression protects mice from the harmful effects of a bacterial polysaccharide infusion and the mortality rate of severely ill patients correlates with reduction of the plasma CETP concentration. Thus, the roles played by PLTP and CETP on atherosclerosis and acute inflammation seem contradictory. Therefore, the biological roles of PLTP and CETP must be carefully monitored when investigating drugs that inhibit their activity in the prevention of atherosclerosis.

Protective modulation of carotid atherosclerosis in hyperalphalipoproteinemic individuals.

To determine whether hyperalphalipoproteinemia modifies carotid intima-media thickness (cIMT) and/or influences the relationship of clinical and biochemical parameters with cIMT. This study was conducted on 169 asymptomatic individuals, classified as hyperalphalipoproteinemic (Hyper-A) (Hyper-A, n = 71, HDL-C > or =68 mg/dL) and controls (CTL) (CTL, n = 98, HDL-C >32 and <68 mg/dL). Enzymatic, nephelometric and ultracentrifugation methods were used for biochemical determinations. Hepatic lipase (HL), lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and phospholipids transfer protein (PLTP) activities were measured by radiometric exogenous methods. The prevalence of dyslipidemia, hypertension, smoking, sedentariness, postmenopausal women, coronary artery disease (CAD) and familial history of CAD were determined. High resolution beta-mode carotid ultrassonography was performed. The Hyper-A group was older and had higher frequencies of hypercholesterolemia (40%), hypertension (31%), sedentariness (37%) and postmenopausal women (1%). In Hyper-A individuals, the mean cIMT after adjustment for age and gender was similar between the groups (0.85 +/- 0.24 mm Hyper-A versus 0.69 +/- 0.17 mm CTL). In multivariate models, age was a significant predictor of cIMT in Hyper-A (R (2) = 0.04, p < or = 0.001), independently of other clinical or biochemical factors. In contrast to CTL, where age (R (2) = 0.63 p < or = 0.001), male sex (R (2) = 0.03, p < or = 0.001), blood pressure (R (2) = 0.006, p < or = 0.001) and HDL-C (R (2) = 0.02, p < 0.022) accounted for the cIMT variations. Despite an increased prevalence of cardiovascular risk factors in Hyper-A and resistance of carotid thickness to modulation by metabolic and anthropometric factors (except age), the similarity in cIMT between Hyper-A and healthy individuals emphasizes the atheroprotective effects of HDL.