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.

Down-regulation of single-stranded DNA-binding protein 1 expression induced by HCMV infection promotes lipid accumulation in cells

The objective of this study was to observe the infection of human cytomegalovirus (HCMV) to human umbilical vein endothelial cells, and its effect on the expression of single-stranded DNA-binding protein (SSBP1) and on lipid metabolism in endothelial cells. We screened the differential expression of mRNAs after HCMV infection by suppression subtractive hybridization and the expression levels of SSBP1 mRNA and protein after HCMV infection by real-time PCR and western blot. After verification of successful infection by indirect immunofluorescent staining and RT-PCR, we found a differential expression of lipid metabolism-related genes including LDLR, SCARB, CETP, HMGCR, ApoB and LPL induced by HCMV infection. The expression levels of SSBP1 mRNA and protein after HCMV infection were significantly down-regulated. Furthermore, we found that upregulation of SSBP1 inhibited the expression of atherosclerosis-associated LDLR, SCARB, HMGCR, CETP as well as the accumulation of lipids in the cells. The results showed that the inhibition of SSBP1 by HCMV infection promotes lipid accumulation in the cells.

El ácido nicotínico aumenta el transporte celular de colesterol de las lipoproteínas de alta densidad en pacientes con hipoalfalipoproteinemia / Nicotinic acid increases cellular transport of high density lipoprotein cholesterol in patients with hypoalphalipoproteinemia

Background: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. Aim: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. Material and Methods: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. Results: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. Conclusions: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

Disruption of reproductive development in male rat offspring following gestational and lactational exposure to di-(2-ethylhexyl) phthalate and genistein

Studies of developmental effects of mixtures of endocrine disrupters on the male reproductive system are of great concern. In this study, the reproductive effects of the co-administration of di-2-(ethylhexyl) phthalate (DEHP) and genistein (GEN) during pregnancy and lactation were studied in male rat offspring. Pregnant Sprague-Dawley rats were gavaged from gestation day 3 to postnatal day 21 with vehicle control, DEHP 250 mg/kg body weight (bwyday, GEN 50 mg/kg bwday, GEN 400 mg/kg bwday, and two combinations of the two compounds (DEHP 250 mg/kg bwday + GEN 50 mg/kg bwday, DEHP 250 mg/kg bwday + GEN 400 mg/kg bwday). The outcomes studied were general morphometry (weight, AGD), testicular histology, testosterone levels, and expression at the mRNA level of genes involved in steroidogenesis. Organ coefficient, AGD / body weight1/3 י, serum testosterone concentration and genes involved in steroidogenic pathway expression when exposed to DEHP (250mg/kg bwday), GEN(50mg/kg bwday) or GEN(400mg/kg bwday) alone were not significantly different from the control group. When exposed to (DEHP 250mg/kg bwday +GEN 50mg/kg bwday) together during pregnancy and lactation, serum testosterone concentration, epididymis coefficient and Cypal17a1,Scarb1 m RNA expression significantly decreased compared to the control and GEN(50mg/kg bwday). When exposed to (DEHP 250mg/kg bwday +GEN 400mg/kg bwday) together during pregnancy and lactation, AGD / body weight1/3 י, serum testosterone concentration, testis and epididymis coefficient and Star, Cypal17a1 mRNA expression appeared significantly decreased compared to the control and DEHP/GEN single exposure, together with developmental impairment of seminiferous tubules and seminiferous epithelium. Overall, co-administration of DEHP and GEN during gestation and lactation seem to acts in a cumulative manner to induce the most significant alterations in the neonate, especially with GEN at high dose, although the effect of the DEHP-GEN mixture on adult offspring should be observed further.

Efecto de la administración de triiodotironina y glucagón sobre la expresión hepática del receptor de lipoproteínas de alta densidad y el metabolismo del colesterol en el ratón / Effect of triiodothyronine (T3) and glucagon on hepatic expression of SR-BI and lipoprotein cholesterol metabolism in mice

Introducción: El receptor scavenger clase B tipo I (SR-BI) es un elemento clave en el metabolismo de las HDL, donde su expresión ejerce un importante efecto anti-aterogénico controlando la fase hepática del transporte reverso de colesterol. Así, el estudio de la modulación de la expresión de SR-BI permitiría el desarrollo de nuevas alternativas farmacológicas para el tratamiento de la ateroesclerosis. Objetivo: La meta de nuestro estudio fue determinar el efecto de la triiodotironina (T3) y el glucagón sobre el metabolismo del colesterol HDL y la expresión hepática de SR-BI en el ratón, evaluando simultáneamente su impacto sobre el colesterol total y lipoproteico plasmático y la secreción biliar de colesterol. Métodos: Se utilizaron ratones C57BL/6 tratados con T3 (30 nmol/kg/día) o glucagón (80 µg/día) más los respectivos grupos controles. Después del tratamiento, los animales se anestesiaron para recolección de bilis, plasma y tejido hepático. Los niveles totales de colesterol plasmático y biliar fueron medidos por métodos enzimáticos. El colesterol lipoproteico plasmático se evaluó por fraccionamiento cromatográfico del plasma y medición enzimática del colesterol en cada fracción. La expresión hepática de SR-BI se cuantificó mediante western blot. Resultados: El uso de T3 o glucagón disminuyeron significativamente el colesterol plasmático total y aumentaron el colesterol biliar con respecto al grupo control correspondiente. Las fracciones de colesterol VLDL, LDL y HDL disminuyeron en ambos grupos tratados, con un mayor efecto observado en la fracción HDL. La administración de ambas hormonas aumentaron significativamente los niveles hepáticos de SR-BI. Conclusión: Los resultados establecen que T3 y glucagón disminuyen el colesterol plasmático, predominantemente de tipo HDL, y aumentan la secreción de colesterol biliar en el ratón, probablemente como consecuencia del incremento en la expresión hepática...

Introduction: The scavenger receptor class B type I (SR-BI) plays a key role in the metabolism of high-density lipoprotein (HDL) cholesterol. Its expression has an important anti-atherogenic effect by controlling the hepatic phase of the reverse cholesterol transport pathway in vivo. Thus, the study of the modulation of SR-BI expression may allow the development of new pharmacologic approaches for treatment of atherosclerotic cardiovascular disease. Objective: The goal of this study was to determine the effect of triiodothyronine (T3) and glucagon on HDL metabolism and hepatic expression of SR-BI in mice, evaluating also the impact in total and lipoprotein cholesterol as well as biliary cholesterol secretion. Methods: C57BL/6 mice were treated with T3 (30 nmol/kg/día) or glucagon (80 µg/día) in comparison to appropriate control groups. After treatment, bile, plasma and hepatic tissue were collected for analysis. Total plasma and biliary cholesterol levels were measured by enzymatic methods. Lipoprotein cholesterol was also measured enzymatically after chromatographic separation of plasma samples. The hepatic expression of SR-BI protein was quantified by western blotting. Results: The use of T3 or glucagon significantly decreased total plasma cholesterol levels and increased of biliary cholesterol concentrations compared to control groups. Levels of VLDL, LDL and HDL cholesterol were reduced in both treatment groups, with a more important effect observed in the HDL fraction. Both treatments increased hepatic SR-BI protein levels. Conclusions: These results show that T3 and glucagon decrease plasma cholesterol levels, particularly in HDL, and increase biliary cholesterol secretion in mice, probably as a consecuence of higher hepatic expression of SR-BI, which may have led to facilitated HDL cholesterol transport from plasma into bile.

Scavenger receptors and atherosclerosis

Scavenger receptors were discovered as cell surface proteins capable of binding and internalization of modified lipoproteins. These receptors exhibit a broad ligand binding specificity including potential physiological and pathophysiological ligands other than modified lipoproteins. Different classes of scavenger receptors have been identified, and their relevance in normal and pathological conditions is under investigation. Recent in vitro and in vivo studies strongly support the role of class A and class B scavenger receptors in lipid transport and atherogenesis.