Hyperlipidemias: Lin J

Wang LY, Lin J, Liu S, Chen BS. · Beijing Institute of Heart Lung and Blood Vessel Diseases-Beijing Anzhen Hospital, Affiliated of Capital University of Medical Sciences, Beijing 100029, China. · Yi Chuan Xue Bao. · Pubmed #16078748 No free full text.

Abstract: Familial hypercholesterolemia (FH),which is caused by low-density lipoprotein (LDL) receptor mutation, leads to LDL-R dysfunction and high plasma LDL level and early onset of cardiovascular disease. LDL-R mutation has been regarded as the only cause of FH phenotype. However, evidences from recent studies showed that another six gene mutations can also result in FH like phenotype through different mechanism. Further studies on these genes will clarify the mechanism of plasma LDL regulation and provide the molecular basis for the diagnosis and treatment of patients with FH-like phenotype. This review summarizes recent studies on the molecular basis of FH-like phenotype heterogeneity in the hope of drawing more attention to the disease.

Jian J, Hao X, Deng C, Zhou H, Lin J. · The First Affiliated Hospital, Hunan Collage of Traditional Chinese Medicine, Changsha 410007. · Zhonghua Nei Ke Za Zhi. · Pubmed #11798687 No free full text.

Abstract: OBJECTIVE: To study the effects of Xuezhikang on lipid profile, thromboxane (TX) A(2), prostacyclin (PGI(2)) in patients with hyperlipidemia. METHODS: 91 patients with hyperlipidemia were randomly divided into a treatment group (n = 47, Xuezhikang 1.2 g/d Bid, p.o) and control group (n = 44, gemfibrozil 1.2 g/d Bid, p.o). serum lipids, TXB(2) and 6-Keto-PGF(1alpha) were determined before and 8 weeks after the treatment. RESULTS: (1) After 8 weeks of treatment, the level of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) decreased by 21.6% (P < 0.01) and 33.3% (P < 0. 01) in the Xuezikang group and by 20.4% (P < 0.01) and 24.8% (P < 0.01) in the gemfibrozil group respectively. Serum high density lipoprotein cholesterol (HDL-C) level elevated by 33.7% in the Xuezhikang group (P < 0.01) and 26.9% in the gemfibrozil group (P < 0.01). The effect of Xuezhikang was the same as gemfibrozil. There was no statistically significant difference between the effects of these two drugs. Triglyceride (TG) level decreased by 23.3% in the Xuezhikang group (P < 0.01) and 40.3% in the gemfibrozil group (P < 0.01). TG lowering effect of gemfibrozil was superior to that of Xuezhikang (P < 0.05). (2) The level of lipoprotein (a) [LP (a)] in the plasma decreased by 28.2% (P < 0.01) in the Xuezhikang group and by 4.9% (P > 0.05) in the gemfibrozil group. LP (a) lowering effect of Xuezhikang was superior to that of gemfibrozil (P < 0.01). (3)The Level of thromboxane (TX) B(2) in the plasma decreased by 34.2% in the Xuezhikang group (P < 0.01) and by 8.4% in the gemfibrozil group (P < 0.01). TXB(2) lowering effect of Xuezhikang was superior to that of gemfibrozil (P < 0.01). The level of 6-KetO-PGF(1alpha) in the plasma elevated by 65.4% in the Xuezhikang group (P < 0.01) and by 11.7% in the gemfibrozil group (P < 0.01); the effect of Xuezhikang was superior to that of gemfibrozil (P < 0.01). CONCLUSION: Xuezhikang could markedly decrease the level of TC and LDL-C and elevate that of HDL-C in patients with hyperlipidemia and the effects of Xuezhikang were the same as those of gemfibrozil. TG lowering effect of gemfibrozil was superior to that of Xuezhikang, but Xuezhikang could markedly decrease the level of Lp (a) and regluate the balance between TXA(2) and PGI(2), its effect being superior to that of gemfibrozil.

Pearson TA, Ballantyne CM, Veltri E, Shah A, Bird S, Lin J, Rosenberg E, Tershakovec AM. · University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. · Am J Cardiol. · Pubmed #19166691 No free full text.

Abstract: Inflammation is associated with coronary artery disease (CAD), and statins reduce the inflammatory marker C-reactive protein (CRP). The effects of ezetimibe, alone or in combination with statins, on CRP and low-density lipoprotein (LDL) cholesterol were examined in 2 pooled analyses of randomized, placebo-controlled trials of ezetimibe 10 mg/day in patients with hypercholesterolemia: 6 12-week trials as monotherapy (n = 1,372) and 7 6- to 8-week trials as add-on to baseline statin therapy (n = 3,899). Mean percentage changes from baseline in CRP and LDL cholesterol were examined using analysis of variance in patients with CRP < or =10 mg/L. Effects within subgroups (age, gender, race, body mass index, diabetes mellitus, metabolic syndrome, CAD, baseline CRP or lipids, and statin potency) and correlations between CRP and LDL cholesterol were also examined. Reduction in CRP by ezetimibe monotherapy was numerically greater than with placebo (treatment difference 6%, p = 0.09). Added to statin therapy, ezetimibe was associated with a significant additional reduction in CRP (treatment difference 10%, p <0.001). Treatment effects were generally consistent across subgroups for the 2 analyses. With monotherapy and add-on to statin therapy, LDL cholesterol reduction with ezetimibe was significantly greater than with placebo (treatment differences -19% and -23%, respectively, p <0.001). Spearman's correlation coefficients among baseline values and percentage changes from baseline in CRP and LDL cholesterol ranged from -0.007% to 0.13%. In conclusion, the addition of ezetimibe to statin treatment provides significantly enhanced CRP reductions over and above those achieved with statin monotherapy. Correlations between changes in CRP and changes in LDL cholesterol were weakly positive and significant only when ezetimibe was added to statin treatment. The effects of ezetimibe monotherapy are not well defined. The effects of ezetimibe on CRP were consistent across patient subgroups.

Lütjohann D, von Bergmann K, Sirah W, Macdonell G, Johnson-Levonas AO, Shah A, Lin J, Sapre A, Musliner T. · Department of Clinical Pharmacology, University of Bonn, Bonn, Germany. · Int J Clin Pract. · Pubmed #18822021 No free full text.

Abstract: OBJECTIVE: To assess the long-term efficacy and safety profile of ezetimibe 10 mg/day in patients with homozygous sitosterolemia. METHODS: This was an extension of a multi-centre, randomised, double-blind, placebo-controlled base study in which patients with homozygous sitosterolemia and plasma sitosterol concentrations > 5 mg/dl were randomised 4 : 1 to ezetimibe 10 mg/day (n = 30) or placebo (n = 7) for 8 weeks. Patients who successfully completed the base study with > 80% compliance to study medication were eligible to enter two, successive, 1-year extension studies in which ezetimibe 10 mg/day was administered in an open-label manner. Patients remained on their current treatment regimen (e.g. bile salt-binding resins, statins and low-sterol diet) during the base and extension studies. Patients had to be off ezetimibe therapy for > or = 4 weeks prior to entering the first extension. Efficacy and safety/tolerability parameters were evaluated every 12 and 26 weeks in the first and second years respectively. The primary efficacy end-point was mean percentage change in plasma sitosterol from baseline to study end for the cohort of patients (n = 21) who successfully completed the second extension study. RESULTS: Treatment with ezetimibe 10 mg/day led to significant mean percentage reductions from baseline in plasma concentrations of sitosterol (-43.9%; p < 0.001), campesterol (-50.8%; p < 0.001), low-density lipoprotein (LDL) sterols (-13.1%; p < 0.050), total sterols (-10.3%; p < 0.050) and apolipoprotein (apo) B (-10.1%; p < 0.050). No significant changes from baseline were observed for lathosterol, high-density lipoprotein sterol, triglycerides or apo A-1. Maximal reductions in sitosterol and campesterol occurred within the first 52 weeks of treatment and were sustained for the duration of the study. For LDL sterol, total sterols and apo B, maximal reductions were achieved early (by weeks 4 or 16) and waned slightly through the remainder of the study. Overall ezetimibe 10 mg was well tolerated. CONCLUSION: In patients with homozygous sitoserolemia, long-term treatment with ezetimibe 10 mg/day for 2 years was effective in reducing plasma plant sterol concentrations with an overall favourable safety and tolerability profile.

Lin J, Wang LY, Liu S, Xia JH, Yong Q, Du LP, Pan XD, Xue H, Chen BS, Jiang ZS. · Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China. · Chin Med J (Engl). · Pubmed #18701038 links to  free full text

Abstract: BACKGROUND: Familial hypercholesterolemia (FH), caused by low density lipoprotein (LDL) receptor (LDL-R) gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel LDL-R gene mutation. METHODS: The patient's LDL-R gene coding region was sequenced. The patient's lymphocytes were isolated and the LDL-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient's heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging (MPI). RESULTS: The patient's LDL-R expression, LDL binding and up-take functions were significantly lower than normal control (39%, 63% and 76% respectively). A novel homozygous 1439 C-->T mutation of the LDL-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes. CONCLUSIONS: The LDL-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the LDL-R gene is determined. These data increase the mutational spectrum of FH in China.

Bian C, Lin J, Li XC, Wang YF, Hu HQ, Chen P. · Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. · Scand J Clin Lab Invest. · Pubmed #17852837 No free full text.

Abstract: OBJECTIVE: To clarify whether hypercholesterolaemia can increase vascular endothelial growth factor (VEGF) expression in human umbilical vascular endothelial cells (HUVECs) through the phosphatidylinositol 3-kinase (PI3K) pathway, and whether a special angiotensin II receptor blocker, telmisartan, can attenuate VEGF expression induced by hypercholesterolaemia. METHODS: Levels of VEGF expression, PI3K activity and angiogenesis in vitro were determined by various methods after HUVECs were incubated with hypercholesterolaemic serum or combined with telmisartan and/or wortmannin. RESULTS: We found that hypercholesterolaemic serum (cholesterol > or = 0.08 mmol/L) can increase VEGF expression in HUVECs and that telmisartan cooperates with hypercholesterolaemic serum in promoting VEGF expression. The increased VEGF expression was associated with enhanced PI3K activity and could be significantly inhibited by wortmannin, a potent PI3K inhibitor. Likewise, hypercholesterolaemic serum significantly promoted angiogenesis in vitro, which could be inhibited when PI3K activity was suppressed. CONCLUSIONS: Our study suggests that hypercholesterolaemic serum induces VEGF expression through PI3K in HUVECs and that telmisartan cooperates with hypercholesterolaemia in promoting VEGF expression.

Ose L, Johnson-Levonas A, Reyes R, Lin J, Shah A, Tribble D, Musliner T, Anonymous00247. · Lipid Clinic, Rikshospitalet, Oslo, Norway. · Int J Clin Pract. · Pubmed #17655686 No free full text.

Abstract: The objective of this study was to compare the efficacy and safety profile of ezetimibe/simvastatin (EZE/SIMVA) tablet and SIMVA monotherapy. This was an extension study of a randomised, double-blind, placebo-controlled study in patients with primary hypercholesterolaemia. Protocol-compliant patients who completed the 12-week base study were eligible to enter a randomised, double-blind, 14-week extension study and were administered 1 of 8 daily treatments: EZE/SIMVA 10/10-, 10/20-, 10/40- or 10/80-mg, or SIMVA 10-, 20-, 40- or 80-mg. Patients receiving these treatments during the base study remained on the same treatment in the extension. Patients administered placebo or EZE 10-mg monotherapy during the base study were re-randomised to EZE/SIMVA 10/10 mg or SIMVA 80 mg. The primary analysis was mean per cent change in low-density lipoprotein cholesterol (LDL-C) from baseline to extension study end-point. Mean changes from baseline in LDL-C of -38.8% and -53.7% were observed for pooled SIMVA and pooled EZE/SIMVA respectively. The between treatment difference of -14.9% (95% confidence interval: -16.4, -13.3) was statistically significant (p < 0.001). The incremental LDL-C lowering effect of EZE/SIMVA compared with the corresponding dose of SIMVA alone was consistent across the dose range (p < 0.001 for each between-group comparison). More patients receiving EZE/SIMVA than SIMVA achieved LDL-C concentrations < 100 mg/dl and < 70 mg/dl (p < 0.001 for both goals). EZE/SIMVA was generally well tolerated with a safety profile similar to SIMVA monotherapy. There were no significant between-group differences in the incidences of clinically significant elevations in liver transaminase or creatine kinase levels. In conclusion, EZE/SIMVA had a comparable safety and tolerability profile and was more efficacious than SIMVA monotherapy for up to 6 months.

Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard CB, Spiegelman BM. · Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. · Cell. · Pubmed #15680331 No free full text.

Abstract: The PGC-1 family of coactivators stimulates the activity of certain transcription factors and nuclear receptors. Transcription factors in the sterol responsive element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. We show here that high-fat feeding, which induces hyperlipidemia and atherogenesis, stimulates the expression of both PGC-1beta and SREBP1c and 1a in liver. PGC-1beta coactivates the SREBP transcription factor family and stimulates lipogenic gene expression. Further, PGC-1beta is required for SREBP-mediated lipogenic gene expression. However, unlike SREBP itself, PGC-1beta reduces fat accumulation in the liver while greatly increasing circulating triglycerides and cholesterol in VLDL particles. The stimulation of lipoprotein transport upon PGC-1beta expression is likely due to the simultaneous coactivation of the liver X receptor, LXRalpha, a nuclear hormone receptor with known roles in hepatic lipid transport. These data suggest a mechanism through which dietary saturated fats can stimulate hyperlipidemia and atherogenesis.

Lin J, Yan GT, Hao XH, Zhang K, Wang LH, Xue H. · Research Laboratory of Biochemistry, Basic Medical Institute, General Hospital of P.L.A., Beijing, PR China. · J Immunoassay Immunochem. · Pubmed #15038616 No free full text.

Abstract: Orexin-A was labeled by 125I using the chloramine-T method, and was purified with a Sephadex G-25 chromatographic column. The reaction between antigen and antibody was carried out by a one-step balance method and was incubated at 4 degrees C for 24 hours, then bonded and free antigen were separated by PR reagent. The detection range of this RIA is 21-2000 pg/mL; the lowest detection level is 21 pg/mL. The intra-assay and inter-assay variations were 7.8% and 9.7%, respectively. Plasma orexin-A levels of 30 normal individuals and 30 patients with hyperlipidemia (serum triglyceride > 1.7 mmol/L and serum total cholesterol > 5.7 mmol/L) were detected by this RIA, while orexin-A levels of plasma and hypothalamus in rat intestinal ischemia-reperfusion injury model were also measured. Plasma orexin-A levels of normal individuals was 338.48 +/- 20.24 pg/mL, while those of patients with hyperlipidemia were 343.51 +/- 15.49 pg/mL; there were no significant differences between these two groups t = -0.1976; P = 0.8441. We also found that orexin-A levels of rat plasma and hypothalamus did not express a significant change during the early stages of intestinal ischemia-reperfusion injury. These results have shown that this orexin-A radioimmunoassay is stable, simple, and specific, being sensitive enough to test orexin-A levels in human plasma, rat plasma, and hypothalamus.

Lin J, Wang LY, Liu S, Pan XD, Du LP, Shi FR, Qin YW, Zhao Q, Guo HY. · Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, PR China. · Zhonghua Yi Xue Yi Chuan Xue Za Zhi. · Pubmed #14767901 No free full text.

Abstract: OBJECTIVE: To identify the mutation of low density lipoprotein receptor(LDLR) gene in a large Chinese family with familial hypercholesterolemia(F H) and make a discussion on the pathogenesis of FH at the molecular level. METHODS: Investigations were made on a patient with the clinical phenotype of homozygous FH and his parents for mutations of promoter and all 18 exons of LDLR gene. Screening was carried out using Touch down PCR and a g arose gel electrophoresis, combined with DNA sequence analysis. The results were compared with the normal sequences in GenBank and FH database (www.ucl.uk/fh) t o find the mutation. Then the mutation was identified in other members of the family. In addition, the authors screened the apolipoprotein B(100) (apoB(100)) gene f or known mutations (R3500Q) that cause familial defective apoB(100) (FDB) by PCR-RFLP. RESULTS: A novel homozygous IN III 5' GT --> AT mutation in the splice donor of LDLR intron 3 was detected in the homozygote propositus with FH. The mutation was also identified in four heterozygous carriers in his family. No mutations R3500Q of apoB(100)were observed. CONCLUSION: A homozygous G --> A splice mutation in LDLR gene was first reported. The change of the splice donor in LDLR intron 3 may cause skipping of exon 3, which is responsible for FH. Perhaps it is a particular pathogenesis for Chinese people.

Cao S, Wang L, Qin Y, Lin J, Wu B, Liu S, Pan X, Du L, Chen B. · Laboratory of Infection and Immunity, Capital Institute of Pediatrics, Beijing 100020, China. · Chin Med J (Engl). · Pubmed #14570618 links to  free full text

Abstract: OBJECTIVE: To screen the point mutation of the low-density lipoprotein receptor (LDL-R) gene in Chinese familial hypercholesterolemia (FH) patients, characterize the relationship between the genotype and the phenotype and discuss the molecular pathological mechanism of FH. METHODS: A patient with clinical phenotype of homozygous FH and her parents were investigated for mutations in the promoter and all eighteen exons of the LDL-R gene. Screening was carried out using Touch-down PCR and direct DNA sequencing; multiple alignment analysis by DNASIS 2.5 was used to find base alteration, and the LDL-R gene mutation database was searched to identify the alteration. In addition, the apolipoprotein B gene (apo B) was screened for known mutations (R3500Q) that cause familial defective apo B100 (FDB) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Two new heterozygous mutations in exons 4 and 9 of the LDL-R gene were identified in the proband (C122Y and T383I) as well as her parents. Both of the mutations have not been published in the LDL-R gene mutation database. No mutation of apo B100 (R3500Q) was observed. CONCLUSION: Two new mutations (C112Y and T383I) were found in the LDL-R gene, which may result in FH and may be particularly pathogenetic genotypes in Chinese people.

Lin J, Peng F, Zeng K, Wu K, Kang Q. · Department of Cardiology, Fujian Institute of Hypertension, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #12609058 No free full text.

Abstract: OBJECTIVE: To investigate the relationship between insulin resistance (IR) and postprandial abnormal metabolism of serum triglyceride-rich lipoprotein in essential hypertension (EH). METHODS: In 44 patients with EH and 22 normal subjects (NS). Total cholesterol, HDL cholesterol, LDL cholesterol, apoliprotein AI and apoliprotein B in fasting serum and serum triglyceride before and 2, 4, 6, 8 hours after a standardized fat loading were measured. Triglyceride peak response (TGPR) and the area under triglyceride curve (TG-AUC) over 8 hours were taken as the index of abnormal TG metabolism. Standardized 75 g oral glucose tolerance test was carried, the area under insulin curve (IS-AUC) over 3 hours and insulin sensitivity index were taken as the index of insulin sensitivity. RESULTS: TGPR and TG-AUC were higher in EH than those in NS (TGRP: 4.14 mmol/L +/- 3.0 mmol/L vs 2.06 mmol/L +/- 1.32 mmol/L, P < 0.01; TG-AUC: 20 mmol/L +/- 6 mmol/L vs 10 mmol/L +/- 4 mmol/L, P < 0.05). 65.9% of EH had postprandial abnormal serum triglyceride metabolism. IS-AUC was higher in EH than that in NS, and ISI was lower in EH than that in NS. The incidence of IR in EH was 61%. 44 EH were categorized into 2 groups according to insulin sensitivity: EH with IR (n = 27) and EH with normal insulin sensitivity (NIS, n = 17). TGPR and TG-AUC in EH with IR were significantly higher than those in EH with NIS (TGPR: 5.25 mmol/L +/- 3.03 mmol/L vs 3.16 mmol/L +/- 1.46 mmol/L, P < 0.05; TG-AUC: 25 +/- 13 mmol/L vs 13 +/- 7 mmol/L, P < 0.01). No significant difference was found between EH with NIS and NS (P > 0.05). TG-AUC and TRPG was positively related to IS-AUC and negatively related to ISI. CONCLUSION: Patients with EH had postprandial abnormal serum triglyceride metabolism, insulin resistance may aggravate postprandial triglyceride metabolism in EH.

Markowitz GS, Lin J, Valeri AM, Avila C, Nasr SH, D'Agati VD. · Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. · Hum Pathol. · Pubmed #12203216 No free full text.

Abstract: Idiopathic nodular glomerulosclerosis (ING) is an enigmatic condition that resembles nodular diabetic glomerulosclerosis but occurs in nondiabetic patients. We reviewed clinicopathologic features, immunohistochemical profiles, and outcomes in 23 patients with ING diagnosed from among 5,073 native renal biopsy samples (0.45%) at Columbia University from January 1996 to March 2001. This cohort, in which diabetes mellitus was excluded, consisted predominantly of older (mean age, 68.2 years) white (73.9%) men (78.3%). Clinical findings at presentation included renal insufficiency in 82.6% (mean serum creatinine = 2.4 mg/dL), proteinuria (> 3 g/d in 69.6%; mean 24-hour urine protein = 4.7 g/d), and-less frequently-full nephrotic syndrome (21.7%). There was a high prevalence of hypertension (95.7%; mean = 15.1 +/- 3.4 years), smoking (91.3%; mean = 52.9 +/- 6.9 pack-years), hypercholesterolemia (90%), and extrarenal vascular disease (43.5%). All 23 patients had prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis, and arteriolosclerosis. Immunohistochemical staining for CD34, a marker of endothelial cells, showed an increased number of vascular channels within ING glomeruli compared with normal controls. Follow-up data were available for 17 patients, 6 of whom reached end-stage renal disease (ESRD) (35.3%). By Kaplan-Meier estimates, the median time after biopsy to ESRD was 26 months. Predictors of progression to ESRD included continuation of smoking (P =.0165), lack of angiotensin II blockade (P =.0007), degree of tubular atrophy and interstitial fibrosis (P =.0517), and degree of arteriosclerosis (P =.0096). In conclusion, ING is a progressive vasculopathic lesion linked to hypertension and cigarette smoking.