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OBJECTIVES@#Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD.@*METHODS@#This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 μmol/L olanzapine (low-dose group), 50 μmol/L olanzapine (medium-dose group), and 100 μmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 μmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively.@*RESULTS@#After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups (P>0.05). Olanzapine dose-dependently increased the plasma TG, ALT and AST levels, and reduced plasma ApoA5 levels (all P<0.05), whereas there was no significant difference in plasma cholesterol (HDL-C, LDL-C, and TC) levels among the 3 groups (all P>0.05). Olanzapine dose-dependently up-regulated ApoA5 protein levels in liver tissues (all P<0.05), but there was no significant change in ApoA5 mRNA expression among groups (P>0.05). In the control group, the structure of liver tissues was intact, the morphology of liver cells was regular, and only a few scattered lipid droplets were found in the cells. In the olanzapine-treated group, there was a large amount of lipid deposition in hepatocytes, and cells were balloon-like and filled with lipid droplet vacuoles. The nucleus located at the edge of cell, and the number of lipid droplets was increased significantly, especially in the high-dose group. Likewise, when HepG2 cells were treated with olanzapine for 24 h, the number and size of lipid droplets were significantly elevated in a dose-dependent manner. Moreover, olanzapine dose-dependently up-regulated ApoA5 protein levels in HepG2 cells (all P<0.05), but there was no significant difference in ApoA5 mRNA expression among groups (P>0.05). Compared with the HepG2 cells transfected with scrambled siRNA, the number and size of lipid droplets in HepG2 cells transfected with ApoA5 siRNA were significantly reduced.@*CONCLUSIONS@#The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease.
Subject(s)
Animals , Male , Mice , Apolipoprotein A-V/genetics , Body Weight , Dimethyl Sulfoxide/metabolism , Liver/metabolism , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/chemically induced , Olanzapine/metabolism , RNA, Messenger/metabolism , RNA, Small Interfering , TriglyceridesABSTRACT
Objective:To investigate the role of apolipoprotein A5 (apoA5) in the pathogenesis of obesityrelated hypertriglyceridemia and the related therapeutic effects of metformin.Methods:The ob/ob mice were treated with regular chow diet and metformin for 4 weeks,and the levels of hepatic triglyceride (TG) and apoA5 were measured.Hepatic IAR20 cells were treated with metformin and/or apoA5 siRNAs,and then cellular TG contents and apoA5 expression were determined.Results:High plasma and hepatic levels of apoA5 and TG were found in ob/ob mice.The plasma levels of apoA5 were positively correlated with plasma TG in these mice.Metformin could dosedependently decrease the plasma and hepatic levels of apoA5 and TG in ob/ob mice.Metformin could also dose-dependently reduce cellular TG contents and apoA5 expression,these effects were attenuated by knockdown of apoA5.Conclusion:Hepatic apoA5 is up-regulated in ob/ob mice,which contributes to the elevation of plasma TG.Metformin could inhibit hepatic apoA5 expression,leading to the reduction of the plasma level of TG.
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Objective To investigate the relativity between c.553G/T polymorphism in exon 4 of Apolipoprotein A5 gene and hypertriglyceridemia (HTG) in Zunyi Han Nationality. Methods c.553G/T polymorphism of 103 HTG patients and 165 healthy individuals were tested by polymerase chain reaction and restriction fragment length (PCR-RFLP) assay. The distributions of genotypes and allele frequencies in HTG patients and healthy group were analyzed between Zunyi population and others. Results The genotype frequency of the Apo A5 gene c.553G/T showed statistical difference between patients group and normal groups (P 0.05). In HTG groups, gene frequency of Zunyi was similar to that in Jiangsu (P>0.05), but higher than that in Xinjiang (P 0.05). Conclusion There is relativity between Apo A5 gene c.553G/T polymorphisms and HTG in Zunyi Han nationality and the differences vary across different areas. It could be an independent risk factor for HTG.
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Objective To initially investigate the time - dependent relation between breviscapine with peroxisome proliferator‐ac‐tivated receptor‐alpha(PPAR‐α) ,apolipoprotein A5 (apoA5) and triglyceride(TG) in HepG2 cells in different time points by ob‐serving the effect of breviscapine on the expression and contents of PPAR‐α ,apoA5 and TG in order to lay a certain foundation for further exploring the concrete mechanism for its regulating TG metabolism .Methods On the basis of earlier stage experiment ,100 mmol/L breviscapine was selected to treat the HepG2 cells at different time points (0 ,6 ,12 ,24 ,36 ,48 h) .The levels of PPAR‐αand apoA5 gene and protein ,and the TG content in HepG2 cells were detected .Results Breviscapine could increase the levels of PPAR‐α and apoA5 gene and protein and decrease the TG content in HepG2 cells (P< 0 .05) ,moreover which showed the time -dependence .Conclusion Breviscapine may decrease the TG level in HepG2 cells ,its mechanism may be realized by increasing the expression of PPAR‐α ,thus increacing the expression of apoA5 in HepG2 cell .
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Totally 79 obese children and 64 children with normal body weight were included in the present study.Serum apolipoprotein A5 (ApoA5) and leptin levels were determined by ELISA and fasting insulin by RIA.The clinical data including height,body weight,waist circumference,blood pressure,blood lipid,blood glucose,etc,were collected.Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated.The results showed that compared with normal weight children,both serum leptin and insulin levels were significantly raised in obese children [19.15 (13.01 ～ 25.08) ng/ml vs 3.29 (1.45 ～ 6.02) ng/ml and 15.44 (12.05 ～ 20.26) μg/L vs 10.12 (8.60 ～ 12.60) μg/L,both P＜0.01],while ApoA5 level was significantly lowered [134.5 (105.9 ～ 172.7) ng/ml vs 2005.9(164.3 ～ 265.3) ng/ml,P＜0.01].Serum ApoA5 was negatively correlated with serum leptin and insulin (both P＜0.01).
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Apolipoprotein A5 (ApoA5) is a newly discovered apolipoprotein which is closely associated with high-density lipoprotein (HDL) remodeling. Clinically it demonstrates potent triglyceride reducing effect. Recent studies have found that ApoA5 can increase cholesteroal reverse transportation and HDL function by remodeling HDL, and it can also influence the progression of atherosclerosis in the different ways, showing a potential anti-atherosclerosis effect. Here we briefly review the characteristics of ApoA5 and its potential protective effect against atherosclerosis.
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The PAW-264.7 macrophages,transfected with apolipoprotein A5 ( apoA5 ) adenovirus or LacZ adenovirus,were challenged with liposome (LPS) or acetylated low-density lipoprotein (acLDL).Production of representatiwe inflammatory cytokine was examined by measuring cytokines in the culture medium with ELISA.Foam cells were counted under a fluorescent microscope. Incorporation of H3-labelled cholesterol was used to reflect cholesterol transportation by the macrophages. The cholesterol and triglyceride were measured with a RIA method.apoA5 transfection decreased the secretion of inflammatory cytokine,the formation of foam cells,as well as the cholesterol transportation.In conclusion,apoA5 could attenuate atherosclerosis by inhibiting the production of inflammatory cytokines and the formation of foam cells,and may represent a potential target for the prevention and treatment of atherosclerosis.
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Objective The aim is to investigate the association between coronary heart disease (CHD) and c.553G＞T polymorphism of apolipoprotein A5 (ApoA5) gene and the influence of serum lipid level in the Hah ethnic population of Xinjiang. Methods The polymorphism of ApoA5 gene in 486 patients with CHD and 501 controls was analyzed by methods of polymerase chain reaction and restriction fragment length polymorphism analysis. Level of serum lipid in each patient was detected at the same time. Results There was significant difference in the distribution of genotypes between CHD group and controls group ( x2 = 8.757, P= 0.013 ). Non-conditioned logistic regression analyses, after adjusted for age, gender, smoking, total serum cholesterol, presence of hypertension and diabetes, revealed that individuals who carried T allele (TT + GT genotype) had an increased risk of CHD, compared to GG genotype (OR= 1.753,95%CI: 1.030-2.983, P＜0.05 ). There was also a remarkable difference noticed in the level of serum triglyceride by genotypes in CHD group and control group (t=5.242, P＜0.01; t=-3.499, P=0.001 ). Individuals in the two groups who carried T allele had higher level of serum triglyceride than those carried GG genotype. Individuals in CHD group who carried T allele had higher level of serum total cholesterol than those carried GG genotype (t=-2.465, P=0.014). Conclusion It seemed that the c.553G＞T polymorphism of ApoA5 gene had influenced on the level of serum triglyceride and the total cholesterol among Han population in Xinjiang. c.553G＞T polymorphism was associated with the development of CHD, while T allele might be an influencing risk factor on CHD.
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Objective To study the relationship between severity of coronary artery lesion and serum level of apolipoprotein A5 (ApoA5). Methods The level of serum total cholesterol (TC), triglyceride (TG), high-den-sity lipoprotein cholesterol (HDL-C ), low density lipoprotein cholesterol (LDL-C ), apolipoprotein A1 ( APOA1), apolipoprotein B (APOB) ,Lipoprotein(a) and uric acid(UA) were examined in 114 patients with coronary heart disease(CHD) and 40 healthy control subjects;Enzyme-linked immunosorbent assay (ELISA) methods was used to determine APOA5. The eoronay heart disease patients were divided into tree groups by the severity of coronary artery lesion: that is one, two and three vessel lesion. Results Compared with control group, APOA5, ApoA1, HDL-C lev-el of CHD groups were lower(P <0.01 or P<0.05) ,TG ,LP(a)and UA were higher(P <0.01 or P <0.05) ,the difference of TC, LDL-C and APOB were not significant (P>0.05 ). In the subgroups of CHD patients, The serum APOA5 concentrations were signficant different between the CHD patients and control group( F=18.605 ,P<0.01 ). Along with the severity of coronary artery,the level of ApoA5 concentrations had a lower trend. The level of ApoA5 was negatively correlated with serum TG level ( r=-0.208, P=0.040) and LP (a) ( r=-0.088, P <0.001). The level of APOA5 had a positive correlation with the serum HDL-C (r= 0.241, P = 0.016). Conclusion There is negative correlation between severity of coronary artery lesion and serum level of ApoA5. The decrease of ApoA5 maybe a risk factor.
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PURPOSE: Recent studies using human and mice reported that apolipoprotein A-V (APOA5) gene plays an important role in controlling triglyceride (TG) concentrations. The purpose of the present study was to investigate the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in the APOA5 gene and TG in subjects and to search for possible associations of the APOA5 gene variants and common haplotypes with hypertriglyceridemia (HTG). MATERIALS AND METHODS: We examined the case-control subjects including 100 HTG patients and 243 unrelated healthy control. The genes were screened for SNPs by direct sequencing in 48 genetically unrelated individuals. Six SNPs (-1390C>T, -1020G>A, -3A>G, V150M, G182C and 1259T>C) were genotyped in case and control populations. RESULTS: In this study, our results indicated a strong association between APOA5 SNP -3A>G and G182C and elevated TG levels (p<0.001). Analysis of the SNPs from APOA5 gene has identified major haplotype showing very strong association with HTG, CGGGTT (p<0.001). Likelihood ratio test (LRT) of these six SNPs revealed that haplotypes were strong independent predictors of HTG (p<0.001). Haplotype-trend logistic regression (HTR) analysis revealed a significant association between the CGGGGC (haplotype 2) and CGGGTT (haplotype 4) and HTG (OR=2.48, 95% CI=1.06-5.76 and OR=8.54, 95% CI=2.66-27.42, respectively). CONCLUSION: We confirm that the APOA5 variants are associated with triglyceride levels and the haplotype may be strong independent predictors of HTG among Koreans.
Subject(s)
Female , Humans , Male , Middle Aged , Apolipoproteins A/genetics , Case-Control Studies , Genetic Predisposition to Disease , Haplotypes , Hypertriglyceridemia/genetics , Korea , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Triglycerides/bloodABSTRACT
Apolipoprotein A5(ApoA5)level and other indices were determined in patients with type 2 diabetes mellitus and healthy individuals.Compared to control group,ApoA5 level in the diabetic group was lower (P