Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis

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基于网络药理学分析及实验验证探讨共轭亚油酸治疗特应性皮炎的作用机制

目的 运用网络药理学的方法考察共轭亚油酸改善特应性皮炎的作用机制，并通过动物进行实验验证。方法 借助Swiss Target Prediction、STITCH数据库获取共轭亚油酸的作用靶点，DisGeNET、GeneCards、TTD数据库检索与特应性皮炎相关的靶标，利用Venny 2.1.0工具获取共轭亚油酸与特应性皮炎的交集靶点。采用STRING 11.0数据库联用Cytoscape 3.9.0软件构建交集靶点的蛋白相互作用（PPI）网络，并筛选共轭亚油酸改善特应性皮炎的核心靶点，并进行基因本体（GO）功能富集分析和京都基因与基因组百科全书（KEGG）通路分析。将32只雌性昆明小鼠随机分为对照组、模型组、共轭亚油酸（100 mg/kg）组和地塞米松（0.1 mg/kg）组，每组8只。采用局部涂抹2,4-二硝基氟苯（DNFB）建立特应性皮炎小鼠模型，并比较各组小鼠皮损评分、皮肤组织病理学形态以及Th1/Th2型细胞因子水平。进一步通过免疫组化检测各组小鼠皮损中核心靶点PPARG的表达情况。结果 网络数据库共筛选出共轭亚油酸作用靶点108个，特应性皮炎相关靶点基因1 708个，取交集后得到48个共轭亚油酸可能作用的特应性皮炎靶点。核心靶点与KEGG通路分析结果显示，共轭亚油酸主要作用于过氧化物酶体增殖物激活受体γ（PPARG）、脂联素基因（ADIPOQ）等核心靶点及PPAR信号通路改善特应性皮炎皮损症状。动物实验结果发现，与模型组比较，共轭亚油酸组小鼠皮损评分显著降低，炎症细胞或肥大细胞的浸润明显减轻，Th1/Th2型细胞因子[免疫球蛋白E（IgE）、白细胞介素-4（IL-4）、γ干扰素（IFN-γ）]水平显著降低（P＜0.05、0.01）。免疫组化检测结果则发现，共轭亚油酸能显著性上调特应性皮炎小鼠皮损中PPARG的表达。结论 通过网络药理学和动物实验初步验证了共轭亚油酸对特应性皮炎的改善作用及其可能的作用机制，为共轭亚油酸后续深入基础实验研究和临床合理应用提供科学依据。     

Investigation of the Lith6 candidate genes APOBEC1 and PPARG in human gallstone disease.

BACKGROUND: Genetic susceptibility contributes to the aetiology of gallbladder diseases as shown by multiple epidemiological studies. A major gallstone susceptibility locus (Lith6) was identified in 2003 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in apolipoprotein B mRNA-editing protein (APOBEC1) and peroxisome proliferator-activated receptor gamma (PPARG) are located in this interval. AIMS: To investigate APOBEC1 and PPARG as candidate genes for common symptomatic gallstone disease in humans. PATIENTS AND METHODS: Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset 50) were compared with 718 sex-matched control individuals. An independent additional sample included 368 gallstone patients and 368 controls. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms were genotyped for PPARG (N=32) and APOBEC1 (N=11). RESULTS: The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.45. No evidence of association of the two genes in the single-point tagging markers, coding variants and in the sliding window haplotype analysis was detected (all nominal single point P-values >0.04). A logistic regression analysis including age, sex and BMI as covariates was also negative (nominal P-values > or =0.08). CONCLUSIONS: In the investigated German samples, no evidence of association of APOBEC1 and PPARG with gallstone susceptibility was detected. Systematic fine mapping of the complete Lith6 region is required to identify the causative genetic variants for gallstone in mice and humans.     

The Pro12Ala variant at the peroxisome proliferator-activated receptor γ gene and change in obesity-related traits in the Diabetes Prevention Program

Aims/hypothesis Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA. Methods We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomised clinical trial of treatment with metformin (n = 989), troglitazone (n = 363) or lifestyle modification (n = 1,004) vs placebo (n = 1,000) for diabetes prevention in high-risk individuals. Results At baseline, Ala12 carriers had larger waists (p < 0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p = 0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p = 0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p = 0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p < 0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p = 0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p ≤ 0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p = 0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p = 0.04) was also observed, which was most evident with metformin treatment (p < 0.001). Conclusions/interpretation Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992). Electronic supplementary material The online version of this article (doi: ) contains a full list of the Diabetes Prevention Program investigators, which is available to authorised users.     

Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population

Background KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes. Methods We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG, and HNF4A by genotyping them using ABI SNaPshot Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects. Results rs5219（E23K） in KCNJ11 was associated with genetic susceptibility to type 2 diabetes （OR=1.400 with 95% CI 1.117 1.755, P=0.004 under an additive model, 0R=1.652 with 95% CI 1.086 2.513, P=0.019 under a recessive model, and OR=1.521 with 95% Cl 1.089 2.123, P=0.014 under a dominant model） after adjusting for sex and body mass index （BMI）. We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 （Pro12Ala） and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion （P=0.005） after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin （P=-0.004 under an additive model for rs2144908; and P=0.001 under a dominant model for rs2144908） after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala. Conclusions Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.     

Lack of genetic association between PPARG gene polymorphisms and Finnish late-onset Alzheimer's disease

Single nucleotide polymorphisms (SNPs) in diabetes related peroxisome proliferator-activated receptor gamma (PPARG) gene were investigated with a case-control approach. To examine the genetic association of this gene with Alzheimer's disease (AD) risk, we used the TaqMan technique to genotype eight SNP sites for PPARG gene, in 538 Finnish AD cases and 672 controls and conducted a single allele and genotypic distribution comparison as well as estimated haplotype frequencies between cases and controls. No significant differences in AD risk were found in single SNP and haplotype analyses for PPARG gene between the study groups. We conclude that PPARG gene does not play a major role in the genetic predisposition to AD in the Finnish population.