Hyperlipidemias: Zhang W

Wang A, Yu BN, Luo CH, Tan ZR, Zhou G, Wang LS, Zhang W, Li Z, Liu J, Zhou HH. · Department of Health Toxicology, School of Public Health, Pharmacogenetics Research Institute, Central South University, Changsha, Hunan, 410078, China. · Eur J Clin Pharmacol. · Pubmed #15650881 No free full text.

Abstract: OBJECTIVES: To determine the frequencies of CYP3A4 alleles (CYP3A4*4,*5 and *6) in Chinese hyperlipidemic patients and to observe the impact of CYP3A4*4 (Ile118Val) genetic polymorphism on the lipid-lowering effects of simvastatin and on the activity of CYP3A4. METHODS: From hospitalized and non-hospitalized patients, 211 unrelated hyperlipidemic patients were recruited for genotyping. CYP3A4 genotypes were determined by means of polymerase chain reaction and restriction fragment length polymorphism analysis. Of the non-hospitalized hyperlipidemic patients, 8 with CYP3A4*1/*1 and 8 with CYP3A4*1/*4 genotypes were selected to be treated with 20 mg simvastatin daily for 4 weeks. Serum triglycerides (TG), cholesterol (CHO) and low-density lipoprotein (LDL) levels were determined using an automated analyzer (Hitachi 747, Boehringer Mannheim, Mannheim, Germany). CYP3A4 activity was determined by the ratio of 6-hydroxycortisol to free cortisol (6-OHC/FC) in the morning spot urine with a high-throughput liquid chromatography-tandem mass spectrometry method. RESULTS: Of 211 subjects, 14 (allele frequency 3.32%) were heterozygous for CYP3A4*4 (Ile118Val). Nevertheless, no subjects with a CYP3A4*5 or CYP3A4*6 allele or homozygous for CYP3A4*4 were identified. The ratio of 6beta-OHC/FC was 9.9 +/- 13.7 and 56.6 +/- 35.7 in subjects with the Ile118Val variant (n = 8) and in CYP3A4 wild-type subjects (n = 8), respectively (P = 0.0039). After oral intake of simvastatin 20 mg daily for 4 weeks, the change of serum lipids in CYP3A4*1/*1 and CYP3A4*1/*4 groups showed a significant difference, with a mean decrease in triglycerides and total cholesterol of 38.1 +/- 7.6% versus 25.1 +/- 8.3% (P = 0.034) and of 35.8 +/- 9.6% versus 22.0 +/-20.4% (P = 0.0015) (means +/- SD), respectively. We found no statistically significant difference in the reductions of LDL between subjects carrying the *1 and *4 genotypes (29.0 +/- 7.4% versus 36.8 +/- 8.8%, P = 0.0721). CONCLUSIONS: The allele frequency of CYP3A4*4 was 3.32% among the hyperlipidemic patients from the Chinese mainland. CYP3A4*4 was an allelic variant related to a functional decrease of CYP3A4 activity, and *4 expression seemed to increase the lipid-lowering effects of simvastatin.

Zhang W, Wang X, Liu Y, Tian H, Flickinger B, Empie MW, Sun SZ. · Tumor Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Br J Nutr. · Pubmed #18053310 No free full text.

Abstract: Lignans, derived from flaxseed, are phyto-oestrogens being increasingly studied for their health benefits. An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300 or 600 mg/d of dietary secoisolariciresinol diglucoside (SDG) from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved (P < 0.05 to < 0.001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22.0 to 24.38 % respectively (all P < 0.005 compared with placebo). For the 300 mg SDG group, only significant differences from baseline were observed for decreases of TC and LDL-C. A substantial effect on lowering concentrations of fasting plasma glucose was also noted in the 600 mg SDG group at weeks 6 and 8, especially in the subjects with baseline glucose concentrations > or = 5.83 mmol/l (lowered 25.56 and 24.96 %; P = 0.015 and P = 0.012 compared with placebo, respectively). Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and enterolactone were all significantly raised in the groups supplemented with flaxseed lignan. The observed cholesterol-lowering values were correlated with the concentrations of plasma SECO and ED (r 0.128-0.302; P < 0.05 to < 0.001). In conclusion, dietary flaxseed lignan extract decreased plasma cholesterol and glucose concentrations in a dose-dependent manner.

Yu H, Zhang W, Yancey PG, Koury MJ, Zhang Y, Fazio S, Linton MF. · Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #16269665 links to  free full text

Abstract: OBJECTIVE: Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. METHODS AND RESULTS: Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3 to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE(-/-)SR-BI(-/-) mice fed 0.5% probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT-->DKO mice, and mean serum cholesterol levels were reduced by 70% versus DKO-->DKO mice. Lipoprotein profiles and HDL subpopulations in WT-->DKO mice were similar to apoE(+/+)SR-BI(-/-)-->DKO mice and resembled those of SR-BI(-/-) mice. In WT-->DKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKO-->DKO mice. Furthermore, the DKO-->DKO mice died &8 weeks after BMT, whereas WT-->DKO mice exhibited a life span >40 weeks after BMT. CONCLUSIONS: Macrophage apoE is able to rescue the lethal phenotype of apoE(-/-)SR-BI(-/-) mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development.

Zhang W, Lu D, Kawazu S, Komeda K, Takeuchi T. · Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan. · Horm Metab Res. · Pubmed #12439786 No free full text.

Abstract: Diabetes is frequently associated with hyperlipidemia, which results in atherogenic complications. Insulin-dependent diabetes mellitus (IDDM) model BB/Wor//Tky (BB) rats exhibit both hyperglycemia and hyperlipidemia and die within 3 weeks after the onset of diabetes unless insulin therapy is given. We performed insulin gene therapy in BB rats with adenovirus vectors through the tail vein. After infusion, plasma triglyceride levels dropped quickly and maintained low levels for 1 week, whereas blood glucose levels showed a slight decrease. The survival period of diabetic BB rats was prolonged to up to 75 days by infusing insulin gene-expressing adenoviral vectors. We suggest that the control of hyperlipidemia can be a life-saving measure when combined with hyperglycemia control in the treatment of diabetes.