Hyperlipidemias: Wu J

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. · Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100050, China. · Nat Med. · Pubmed #15531889 No free full text.

Abstract: We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.

Zhou Y, Zhang X, Chen L, Wu J, Dang H, Wei M, Fan Y, Zhang Y, Zhu Y, Wang N, Breyer MD, Guan Y. · Department of Physiology and Pathophysiology, Peking University Health Science Center, 38 Xueyuan Rd., Beijing, China. · Am J Physiol Renal Physiol. · Pubmed #18614621 No free full text.

Abstract: Hyperlipidemia is one of the major features of nephrotic syndrome (NS). Although many factors have been implicated in the pathogenesis of NS-related dyslipidemia, the underlying mechanisms remain largely uncharacterized. The present study was designed to examine the gene profile associated with lipid metabolism in the livers of nephrotic rats. NS was created in male Sprague-Dawley rats (n = 6) receiving sequential intraperitoneal injections of puromycin aminonucleoside. Analysis by Affymetrix assay, quantitative RT-PCR, and Northern and Western blotting revealed 21 genes associated with cholesterol and fatty acid metabolism. Eight genes involved in cholesterol metabolism, Apo A-I, Acly, Acat, Mpd, Fdps, Ss, Lss, and Nsdhl, were significantly upregulated under NS. Four genes involved in fatty acid biosynthesis, Acc, FAS, ELOVL 2, and ELOVL6, and three critical for triglyceride biosynthesis, Gpam, Agpat 3, and Dgat 1, were significantly upregulated, whereas two genes involved in fatty acid oxidation, Dci and MCAD, were downregulated. Expression of several genes in sterol-regulatory element-binding protein (SREBP)-1 activation was also aberrantly altered in nephrotic livers. The expression and transcriptional activity of SREBP-1 but not SREBP-2 were increased in nephrotic rats as assessed by real-time PCR, immunoblotting, and gel shift assays. The upregulation of hepatic genes involved in cholesterol biosynthesis may play an important role in the pathogenesis of hypercholesterolemia, whereas upregulation of genes participating in hepatic fatty acid and triglyceride biosynthesis and downregulation of genes involved in hepatic fatty acid oxidation may contribute to hypertriglyceridemia in nephrotic rats. Activation of SREBP-1 transcription factor may represent an underlying molecular mechanism of hyperlipidemia in NS.

Yin R, Pan S, Wu J, Lin W, Yang D. · Department of Cardiology, Institute of Cardiovascular Diseases, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, P. R. China. · Exp Biol Med (Maywood). · Pubmed #18367629 links to  free full text

Abstract: Hei Yi Zhuang is an isolated subgroup of the Zhuang minority in China. Little is known about the distribution of apolipoprotein (apo) E genetic variations and its role in lipid metabolism in this population. The present study was undertaken to compare the effect of apoE gene polymorphism on serum lipid levels between the Guangxi Hei Yi Zhuang and Han populations. A total of 873 subjects of Hei Yi Zhuang and 867 participants of Han Chinese were surveyed by a stratified randomized cluster sampling. Genotyping of apoE was performed using polymerase chain reaction and restriction fragment length polymorphism. The frequencies of 2, 3, and 4 alleles were 15.23%, 79.84%, and 4.93% in Hei Yi Zhuang, and 9.23%, 81.43%, and 9.34% in Han (P < 0.001); respectively. The frequencies of 2/ 2, 2/ 3, 2/ 4, 3/ 3, 3/ 4, and 4/ 4 genotypes were 4.70%, 17.86%, 3.21%, 68.16%, 5.50%, and 0.57% in Hei Yi Zhuang, and 2.54%, 9.23%, 4.15%, 70.70%, 12.23%, and 1.15% in Han (P < 0.001); respectively. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and apoB levels were lower in Hei Yi Zhuang than in Han (P < 0.01-0.001), but high-density lipoprotein cholesterol (HDL-C) levels and the ratio of apoA-I to apoB were higher in Hei Yi Zhuang than in Han (P < 0.001 for each). There were significant differences in TC, HDL-C, LDL-C, and apoB levels among the six genotypes in both ethnic groups (P < 0.01-0.001). Hyperlipidemia was positively correlated with age, body mass index, hypertension, alcohol consumption, and apoE allele in both populations (P < 0.05-0.001). TC, LDL-C, and apoB levels were positively correlated, and HDL-C levels were negatively associated with apoE genotypes in both ethnic groups (P < 0.001 for all). The differences in the lipid profiles between Hei Yi Zhuang and Han Chinese might partly attribute to the differences in apoE genotypic and allelic frequencies.

Wu J, Province MA, Coon H, Hunt SC, Eckfeldt JH, Arnett DK, Heiss G, Lewis CE, Ellison RC, Rao DC, Rice T, Kraja AT. · Division of Statistical Genomics, Washington University School of Medicine, Campus Box 8506, 4444 Forest Park Boulevard, Saint Louis, MO 63108, USA. · BMC Genet. · Pubmed #17845730 links to  free full text

Abstract: BACKGROUND: Use of anti-hyperlipidemic medications compromises genetic analysis because of altered lipid profiles. We propose an empirical method to adjust lipid levels for medication effects so that the adjusted lipid values substitute the unmedicated lipid values in the genetic analysis. RESULTS: Published clinical trials were reviewed for HMG-CoA reductase inhibitors and fibric acid derivatives as mono-drug therapy. HMG-CoA reductase inhibitors showed similar effects in African Americans (AA) and non-African Americans (non-AA) for lowering total cholesterol (TC, -50.7 mg/dl), LDL cholesterol (LDL-C, -48.1 mg/dl), and triglycerides (TG, -19.7 mg/dl). Their effect on increasing HDL cholesterol (HDL-C) in AA (+0.4 mg/dl) was lower than in Non-AA (+2.3 mg/dl). The effects of fibric acid derivatives were estimated as -46.1 mg/dl for TC, -40.1 mg/dl for LDL-C, and +5.9 mg/dl for HDL-C in non-AA. The corresponding effects in AA were less extreme (-20.1 mg/dl, -11.4 mg/dl, and +3.1 mg/dl). Similar effect for TG (59.0 mg/dl) was shown in AA and non-AA. The above estimated effects were applied to a multipoint variance components linkage analysis on the lipid levels in 2,403 Whites and 2,214 AA in the HyperGEN study. The familial effects did vary depending on whether the lipids were adjusted for medication use. For example, the heritabilities increased after medication adjustment for TC and LDL-C, but did not change significantly for HDL-C and TG. CONCLUSION: Ethnicity-specific medication adjustments using our empirical method can be employed in epidemiological and genetic analysis of lipids.

Xu G, Huang X, Qiu L, Wu J, Hu Y. · Department of Nutrition and Food Hygiene, Nantong University, 19 Qixiu Road, Nantong, Jiangsu, China 226001. · Asia Pac J Clin Nutr. · Pubmed #17392126 No free full text.

Abstract: It has been reported that plasma and liver cholesterol concentrations decrease when animals are fed with chitosan, but the mechanism is unclear. Four wk old male SD (Sprague-Dawley) rats were fed a commercial rat diet (cholesterol-free diet, negative control, NC), cholesterol-enriched diet containing 5% of chitosan (CH) or cholesterol-enriched diet containing 5% of cellulose (CE) and 5% of lard for 12 weeks. We would investigated the effects of chitosan on plasma and liver cholesterol levels, liver weight, bile acids concentrations of fecal and hepatic LDL receptor mRNA expression. The results showed that chitosan could decrease levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in plasma (p<0.05), and TC, total triglyceride (TG) in liver (p<0.05), and increase fecal bile acids excretion (p<0.05), but the levels of TG and HDL-C in plasma was unchanged (p>0.05). In addition, the result of RT-PCR test showed that saturated fat and cholesterol fed could significantly induce the reduction of LDL receptor mRNA levels, while chitosan could increase hepatic LDL receptor mRNA levels. This study suggested that chitosan improve lipid metabolism by regulating TC and LDL-C by upregulating of hepatic LDL receptor mRNA expression, increasing the excretion of fecal bile acids.

Yuan L, Tu D, Ye X, Wu J. · Chemistry institute of Pharmaceutical Resource, Southwest University, Chongqing, 400716, People Republic of China. · Plant Foods Hum Nutr. · Pubmed #17031605 No free full text.

Abstract: Hypocholesterolemic and hypoglycemic activities of Coptis chinensis franch inflorescence (Coptis inflorescence) were studied using animal models. Serum total and LDL cholesterol of rats fed a diet containing 1% cholesterol and 0.5% cholic acid increased, as compared with those of rats fed a normal diet. The level of total and LDL cholesterol were reduced markedly in a dose dependent manner, in rats given Coptis inflorescence extract orally at doses of 0.25, 0.5 g/kg.day for 4 weeks. In diabetic rats induced by alloxan, Coptis inflorescence extract showed a significant (p < 0.05) blood sugar lowering activity at all experimented doses (0.125, 0.25 and 0.5 g/kg.day). The highest reduction of blood sugar was about 58% when the rats were given Coptis inflorescence extract orally at a dose of 0.5 g/kg.day for 3 weeks. The 100 g dried water extract of Coptis inflorescence contained 8.11 g total alkaloid, 3.34 g berberin, 1.08 g palmatine and 0.66 g jatrorrhizine, which had long been identified as active compounds in Coptis chinensis franch root (Coptis root). Thus, the results suggest that Coptis inflorescence would be effective in the prevention and management of coronary artery disease by lowering serum cholesterol and blood sugar.

Yin R, Chen Y, Pan S, He F, Liu T, Yang D, Wu J, Yao L, Lin W, Li R, Huang J. · Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital, Guangxi Medical University, Nanning, China. · Arch Med Res. · Pubmed #16824940 No free full text.

Abstract: BACKGROUND: Hyperlipidemia is a risk factor for atherosclerotic events. Differences in lipid levels may exist in different races. Han is the largest group and Zhuang is the largest minority among the 56 nationalities in China. Geographically and linguistically, Zhuang can be classified into 43 ethnic subgroups, among which Hei Yi (means black worship and black dress) Zhuang, living in Napo County bordering northeast Vietnam and with a population of about 50,000, is a special ethnic group, and the most conservative with a unique culture. Little is known about the lipid levels in this population. The aim of this study was to compare the lipid levels, prevalence of hyperlipidemia, and risk factors in Hei Yi Zhuang and Han populations. METHODS: A total of 1068 people of Hei Yi Zhuang nationality were surveyed by a cluster sampling. Blood pressure, height, weight, serum lipid and apolipoprotein (Apo) levels were measured, and body mass index (BMI) was calculated. The results were compared with those in 933 people of Han nationality who also live in that district. RESULTS: The levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and Apo B in Hei Yi Zhuang nationality were significantly lower than those in Han nationality (p <0.05-0.001), but the levels of high-density lipoprotein cholesterol and the ratio of Apo A1 to Apo B in Hei Yi Zhuang nationality were significantly higher than those in Han nationality (p <0.001 and 0.05, respectively). The prevalence rates of hypercholesterolemia, hypertriglyceridemia, and hyperlipidemia in Hei Yi Zhuang and Han nationalities were 25.00 vs. 28.72% (p >0.05), 12.45 vs. 14.36% (p >0.05), and 31.37 vs. 35.91% (p <0.05); respectively. The prevalence of hyperlipidemia in Hei Yi Zhuang or Han population was positively correlated with age, BMI, blood pressure, and alcohol consumption (p <0.05-0.001), respectively, but was not associated with gender or cigarette smoking in both nationalities (p >0.05). CONCLUSIONS: The current study reveals that there were significant differences in lipid levels and prevalence of hyperlipidemia between Hei Yi Zhuang and Han ethnic groups, but no significant differences in the detected risk factors for hyperlipidemia between the two ethnic groups, which might result from the comprehensive role of different dietary habits, life style, and level of physical activity, as well as genetic background.

Zhao SP, Wu ZH, Wu J, Hong SC, Deng P. · Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, PR China. · J Cardiovasc Pharmacol. · Pubmed #16044030 No free full text.

Abstract: Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine involved in atherogenesis. Adipose tissue is an important source of endogenous TNFalpha production. The aim of this study was to evaluate the effect of atorvastatin on TNFalpha serum concentration and mRNA expressions of subcutaneous adipose in hypercholesterolemic rabbits. Sixteen rabbits fed with a high-cholesterol diet for 8 weeks were randomly divided into 2 groups: (1) the high-cholesterol group (n=8) was maintained on a high-cholesterol diet for 6 weeks; (2) the atorvastatin group (n=8) had the same high-cholesterol diet plus atorvastatin (2.5 mg/kg/d) for 6 weeks. A control group (n=5) was fed with a normal diet for 14 weeks. Subcutaneous adipose was collected for mRNA analysis. Additionally, the direct effect of atorvastatin on TNFalpha release and mRNA expression was assayed in primary rabbit adipocytes. TNFalpha levels in serum and adipocyte culture supernatant were measured by ELISA. RT-PCR was used to evaluate TNFalpha mRNA expression in adipose and adipocytes. Serum TNFalpha concentration was significantly associated with serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) (both P<0.01). Compared with the control group, rabbits fed with a high-cholesterol diet showed higher levels of TNFalpha serum concentration and mRNA expression of adipose, both of which were significantly reduced by atorvastatin treatment (both P<0.05). TNFalpha mRNA expressions of adipose were significantly correlated with circulating TNFalpha levels among the 3 groups (r=0.51, P<0.05). Atorvastatin dose-dependently inhibited lipopolysaccharide (LPS)-induced TNFalpha secretion and mRNA expression in cultured adipocytes. In conclusion, atorvastatin can directly inhibit TNFalpha expression and secretion in adipocytes. Atorvastatin reduced TNFalpha serum concentration in hypercholesterolemic rabbits, which might be because of its cholesterol-lowering effect and direct inhibition of TNFalpha expression in adipose.

Zhao SP, Wu J, Zhang DQ, Ye HJ, Liu L, Li JQ. · Department of Cardiology, The Second Xiangya Hospital of Central South University, Middle Ren-Min Road No. 86, Changsha, Hunan 410011, PR China. · Atherosclerosis. · Pubmed #15530897 No free full text.

Abstract: BACKGROUND: CD36 as a fatty acid transporter is predominantly expressed in adipocytes. We studied whether adipocytes could uptake and degrade OxLDL through CD36 and explored the effect of fenofibrate on OxLDL uptake in adipocytes from hypercholesterolemia rabbits. METHODS: Subcutaneous adipose tissues were collected from normal, high-cholesterol and high-cholesterol plus fenofibrate treatment rabbits for adipocytes culture. CD36 and peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression were evaluated by RT-PCR. RESULTS: Cellular expression of CD36 was confirmed during differentiation of adipose cell by RT-PCR. Upon incubation at 37 degrees C, (125)I-OxLDL was endocytosed in a dose-dependent fashion and underwent lysosomal degradation by adipocytes. In binding experiments at 4 degrees C, (125)I-OxLDL exhibited specific and saturable binding to adipocytes (K(D) = 4.2 microg/mL). The endocytic uptake and degradation of (125)I-OxLDL by adipocytes were inhibited by 56 and 54% with anti-CD36 antibody. Fenofibrate treatment enhanced the (125)I-OxLDL uptake and degradation and up-regulated CD36 mRNA expression in adipocytes and suppressed PPARgamma mRNA expression in adipose tissue from hypercholesterolemia rabbits. CONCLUSION: CD36 plays a novel role in adipose tissues and adipocytes possibly involve in clearance of OxLDL in blood. Fenofibrate treatment improved the OxLDL uptake and degradation in adipocytes from hypercholesterolemia rabbits.

Zhao SP, Xiao ZJ, Li QZ, Nie S, Tan LM, Jiang B, Wu J. · Department of Cardiology, Xiangya Second Hospital, Central South University, Changsha 410011, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #15500734 No free full text.

Abstract: OBJECTIVE: To investigate whether ATP-binding cassette transporter 1 (ABCA1) R219K genetic variation is correlated with blood lipids. METHOD: Specimens of peripheral blood were collected from 692 patients with cerebral apoplexy, aged 62 +/- aged 12, and 352 sex- and age-matched persons without cardio-cerebro-vascular disease. Polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP) was used to determine the ABCA1 genotype: RR type (177 bp), RK type (177 bp, 107 bp, and 70 bp); and KK type (107 bp and 70 bp). The RR and KK type products were sequenced. RESULTS: The level of HDL-C showed an upward trend in the sequence of RR, RK, and KK genotypes with a significant difference between RR genotype (1.3 mmol/L +/- 0.4 mmol/L) and KK genotype (1.4 mmol/L +/- 0.4 mmol/L), especially in the males. The levels of TG tended downward in the sequence of RR, RK, and KK genotypes, however, without a significant difference between any 2 genotypes. Linear regression analysis showed that the HDL-C level was positively correlated with age in the noncarriers of ABCA1R219K genetic variation (RR genotype), and the TC level was negatively correlated with age in the carriers (RK + KK genotype). In the cohort aged </= 70 the HDL-C level was higher in carriers than in noncarriers. CONCLUSION: ABCA1R219K genetic variation results in a beneficial profile of blood lipids, more evident in males. RK + KK genotype is more pronounced in the individuals aged </= 70.

Zhao SP, Wu J. · Department of Cardiology, The Second Xiangya Hospital of Central South University, middle Ren-Min road No. 86, Changsha, Hunan 410011, PR China. · Clin Chim Acta. · Pubmed #15313152 No free full text.

Abstract: BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is produced by cells of the macrophage-monocyte lineage and by adipocytes. It may provide the link between inflammation and atherosclerosis. The aim of this study was to evaluate the effect of fenofibrate on serum TNF-alpha concentration and TNF-alpha secretion by adipocytes from hypercholesterolemic rabbits. METHODS: Ten male New Zealand white rabbits were fed with high-cholesterol diet for 8 weeks, and were randomly divided into two groups: (1) high cholesterol group: maintained cholesterol diet for 4 weeks; and (2) fenofibrate treated group: the same cholesterol diet supplemented with fenofibrate (30 mg/kg/day) for 4 weeks. Control group was fed with normal diet for 12 weeks. Subcutaneous adipose was collected for adipocytes culture. TNF-alpha concentrations in serum and adipocytes culture supernatant were measured by ELISA. RESULTS: Rabbits fed with high-cholesterol diet showed higher serum levels of total cholesterol, low density lipoprotein cholesterol than those fed with normal diet (P<0.001). Fenofibrate treatment did not change serum lipid levels during the feeding period, but decreased high cholesterol diet-induced increases in body weight by 19% and serum TNF-alpha concentration by 44.7% in fenofibrate treated group compared with high cholesterol group (P<0.05). The decreased levels of TNF-alpha correlated with the weight loss (r=0.35, P<0.05). Fenofibrate (10 to 100 micromol/l) significantly reduced release of TNF-alpha in adipocytes (P<0.05). Meanwhile serum TNF-alpha concentration were significantly correlated with TNF-alpha secretion in adipocytes (r=0.51, P<0.05). CONCLUSIONS: Our study indicated that fenofibrate reduced tumor necrosis factor-alpha serum concentration and adipocyte secretion of hypercholesterolemic rabbits. This effect of fenofibrate might contribute to its benefits on the prevention and treatment of atherosclerosis.

Wu J, Zhu YH, Patel SB. · Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of South Carolina, Charleston, South Carolina 29425-2222, USA. · Am J Physiol. · Pubmed #10600799 links to  free full text

Abstract: The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.