Polymorphisms at the SRBI locus are associated with lipoprotein levels in subjects with heterozygous familial hypercholesterolemia

Scavenger receptor, class B, type 1 (SRBI) is a promising candidate gene involved in the pathophysiology of atherosclerosis. We have examined the association of three common polymorphisms at the SRBI locus in 77 subjects who were heterozygous for familial hypercholesterolemia (FH). The alleles represented by polymorphisms in exon 1 and exon 8 were associated with variation in plasma concentrations of fasting triglyceride (TG). Mean plasma TG concentrations for homozygotes for the most common allele, and for heterozygotes and homozygotes for the less common allele were 85 +/- 6, 111 +/- 9 and 135 +/- 22 mg/dl (p = 0.011) for exon 1, and 96 +/- 11, 86 +/- 6 and 134 +/- 13 mg/dl (p = 0.007) for exon 8, after adjustment for age, sex and body mass index. In addition, the exon 8 polymorphism was associated with increased total cholesterol (320 +/- 15, 340 +/- 8 and 388 +/- 18 mg/dl, p = 0.015), very low density lipoprotein (VLDL) cholesterol (18 +/- 2.9, 15.7 +/- 1.6 and 33.4 +/- 3.9 mg/dl, p < 0.001) and low density lipoprotein (LDL) cholesterol (251 +/- 15, 270 +/- 8 and 312 +/- 10 mg/dl, p = 0.041) concentrations. In agreement with animal studies, our data also suggest a role for the SRBI in the metabolism of apolipoprotein B (apoB)-containing lipoproteins in humans. This pathway may constitute a backup mechanism to LDL receptor-mediated pathways for the catabolism of these lipoproteins, which could be particularly relevant in subjects with high levels of apoB-containing lipoproteins, such as those occurring in patients with FH.     

甲状腺素对胃腺癌细胞VLDL-R选择性剪接的影响

目的探讨甲状腺素对低分化胃腺癌细胞MKN45细胞中极低密度脂蛋白受体(VLDL-R)选择性剪接的影响。方法在体外,用一定浓度的甲状腺素与MKN45细胞温育不同时间后,采用RT-PCR和Western印迹技术检测两型VLDL-R mRNA和蛋白质的表达水平,以两型受体的比值间接反映甲状腺素对VLDL-R选择性剪接的影响。结果甲状腺素可明显上调两型VLDL-R的表达,Ⅱ型受体与Ⅰ型受体mRNA的比值随时间延长逐渐增大。结论甲状腺素可显著增强VLDL-R的选择性剪接,表现为Ⅱ型受体表达的增高幅度明显大于Ⅰ型受体。     

Biochemical and immunohistochemical changes in delta-9-tetrahydrocannabinol-treated type 2 diabetic rats

The regulation of glucose, lipid metabolism and immunoreactivities of insulin and glucagon peptides by delta-9-tetrahydrocannabinol (Δ⁹-THC) in diabetes were examined in an experimental rat model. Male Sprague-Dawley rats were divided into four groups: (1) control, (2) Δ⁹-THC treated, (3) diabetic, and (4) diabetic + Δ⁹-THC. The type 2 diabetic rat model was established by intraperitoneal (i.p.) injection of nicotinamide (85 mg/kg body weight) followed after 15 min by i.p. injection of streptozotocin (STZ) at 65 mg/kg of body weight. Δ⁹-THC and Δ⁹-THC treated diabetic groups received 3 mg/kg/day of Δ⁹-THC for 7 days. The immunolocalization of insulin and glucagon peptides was investigated in the pancreas using a streptavidin–biotin–peroxidase technique. High density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), very low density lipoprotein cholesterol (VLDL), triglycerides (TG), total cholesterol (TC) and total protein (TP) levels were measured in serum. Total islet area percent of insulin immunoreactive cells slightly changed in diabetic + Δ⁹-THC rats compared to diabetic animals. However, the area percent of glucagon immunoreactive cells showed a decrease in diabetic + Δ⁹-THC rats compared to that of diabetic animals alone. Serum TC, HDL and LDL levels of diabetes + Δ⁹-THC group showed a decrease compared to the diabetic group. These results indicate that Δ⁹-THC may serve a protective role against hyperlipidemia and hyperglycemia in diabetic rats.     

A comparative study between the effect of 17-β estradiol and antioxidants combination on some menopausal changes in oophorectomised rats

BackgroundAs oxidative stress is proposed to be responsible for many of the menopause associated disorders, antioxidants may play an important role in this situation. The aim of this work was to compare between the effects of oestrogen replacement therapy and antioxidant supplements of vitamin C and low dose of vitamin A on some menopause associated changes in oophorectomised rats.Materials and methodsForty albino female rats were divided into 4 groups: normal control group, oophorectomised group, oophorectomised group treated with 17-β estradiol (oophorectomised + E₂) and oophorectomised group treated with vitamins (oophorectomised + vit).The following were measured: total antioxidant (TAO) and malondialdehyde (MDA), lipid profile, serum insulin, glucose and homeostasis model assessment-insulin resistance (HOMA-IR), bone specific alkaline phosphatase (BALP), urinary hydroxyproline, weight gain and visceral fat.ResultsA positive correlation was found between MDA and low density lipoprotein-cholesterol (LDL) (r = 0.694 and P = 0.000), HOMA-IR (r = 0.691 and P = 0.000.) and BALP (r = 0.563 and P = 0.000) and urinary hydroxyproline level (r = 0.761 and P = 0.000). Those results denoted that OS might be a cause of dyslipidemia, insulin resistance and osteoporosis associated with menopause.Both E₂ and vitamins in oophorectomised rats led to a significant decrease in MDA (F = 33.402, P = 0.000), weight gain, visceral fat (F = 7.589, p = 0.000 and F = 3.748, P = .019, respectively), cholesterol (F = 40.748, P = 0.0001), LDL cholesterol (F = 55.168, P = 0.0001), and significant increase in HDL (F = 18.393, P = 0.0001) and TAO levels (F = 14.781, P = 0.000) compared to oophorectomised rats. Also, both treatments led to a significant decrease of HOMA-IR (F = 18.933, P = 0.000, respectively), BALP (F = 13.202, P = 0.000) and urinary hydroxylproline (F = 220.012, P = 0.000). An interesting finding was detected where oophorectomised rats showed a decrease in triglyceride level which was significantly increased by E₂ administration whereas antioxidant administration produced no change (F = 34.267, P = 0.0001).ConclusionOur results denote similar effects of both E₂ and antioxidant’ supplements (vitamin C and low dose vitamin A) administration in surgically induced menopause in rats regarding oxidative stress, weight gain, atherogenic lipid profile changes, insulin sensitivity and bone turnover. However differences between preclinical and clinical studies must be taken into consideration especially when moving from animal studies to clinical trials.     

Cholesteryl ester transfer protein facilitates the movement of water-insoluble drugs between lipoproteins: a novel biological function for a well-characterized lipid transfer protein

This review article addresses the recently discovered finding that cholesteryl ester transfer protein (CETP) can facilitate the transfer of water-insoluble drugs between different lipoprotein subclasses. This protein, which is often referred to as lipid transfer protein I (LTP I), is involved in the lipid regulation of lipoproteins. It is responsible for the facilitated transfer of core lipoprotein lipids, cholesteryl ester and triglycerides, and approximately one-third of the coat lipoprotein lipid, phosphatidylcholine, between different plasma lipoproteins. The human body appears to recognize exogenous water-insoluble drugs as lipid-like particles, which suggests that these compounds may interact with lipoproteins just like endogenous plasma lipids, and thus their transfer between lipoproteins may be facilitated by plasma CETP. Patients with a variety of diseases (i.e. diabetes, cancer, AIDS) often exhibit hypo- and/or hypercholesterolemia and triglyceridemia, commonly referred to as dyslipidemias, which result in changes in their plasma lipoprotein-lipid composition and concentration. The interaction of water-insoluble drugs with these dyslipidemic lipoproteins may be responsible for the differences seen in the pharmacokinetics and pharmacodynamics of the drug within different diseased patient populations. It is possible that these differences may be linked to the ability of CETP to transfer these compounds from one lipoprotein to another. This review examines the current understanding of the relationship between CETP activity and the lipoprotein distribution of a number of compounds (e.g. amphotericin B and cyclosporine A). It further suggests that additional research will expand our understanding of the role of CETP to explain other functions in lipophilic drug distribution and metabolism.     

氧化极低密度脂蛋白促进猪主动脉平滑肌细胞内脂类堆积的机制及其细胞毒作用

200μg／ml的氧化极低密度脂蛋白（OX－VLDL）与猪主动脉平滑肌细胞（SMC）温育48h后，细胞内甘油三酯（TG）含量为不加脂蛋白对照组的3．2倍（P＜0．01），细胞内总胆固醇（TC）含量为对照组的1．22倍（P＜0．05）。荧光素异硫氰酸酯（FITC）标记OX－VLDL的结合试验表明：SMC可摄取完整的OX－VLDL（Kd=48．82μg／ml，Bmax=2067ng／mgcellprotein）。竞争抑制试验表明，OX－VLDL及正常低密度脂蛋白（N－LDL）均对FITC－OX－VLDL的结合摄取表现出明显的竞争作用，两者的作用相似。以上结果表明，SMC能通过受体途径可饱和性地摄取完整的OX－VLDL，进而形成泡沫细胞。同时还发现OX－VLDL与SMC长时间温育（24h以上）会损伤细胞，造成部分细胞脱落。这对动脉粥样硬化及急性冠状动脉综合征发病机制研究及其预防和治疗都有重要的指导意义。     

Peripheral inflammatory and fibrinolytic markers in adolescents with growth hormone deficiency: relation to postprandial dyslipidemia

OBJECTIVE: To determine whether peripheral inflammatory and fibrinolytic markers are elevated in growth hormone-deficient (GHD) adolescents and associated with increased postprandial lipoproteins. STUDY DESIGN: Fifteen GHD children on GH treatment with a chronologic age of 12.7 +/- 2.5 years and 10 untreated GHD adolescents with a chronologic age of 13.0 +/- 2.6 years were studied. Triglycerides (TG), C-reactive protein (CRP), fibrinogen, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured in the fasting state and 4 hours after ingesting a high-fat meal; 15 healthy adolescents served as controls. RESULTS: Fasting and postprandial TG of untreated GHD children were higher than those in treated subjects and healthy controls. Fasting TNF-alpha, CRP, and fibrinogen concentrations of untreated GHD adolescents were higher than those in healthy controls, but similar to those of GH-treated GHD adolescents. Although fibrinogen levels increased after a high-fat meal in GHD adolescents, CRP, TNF-alpha, and IL-6 concentrations did not increase further. Fasting and postprandial TG of untreated GHD adolescents were positively associated with fasting and postprandial CRP, and with postprandial TNF-alpha and IL-6 concentrations. Fasting TG also correlated positively with fasting fibrinogen concentrations in untreated and treated GHD adolescents. CONCLUSIONS: The pronounced inflammatory response seen in GHD adolescents seems to be associated with the presence of elevated levels of fasting and postprandial TG, which may result in an increased susceptibility for premature atherosclerosis.     

A case control study on HDL associated PON1 enzyme level in Northern Indian type 2 diabetes mellitus patients

Aim

To evaluate the serum paraoxonase 1 activity and determine its association with duration in type 2 Diabetes mellitus patients.