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Germ cell-specific deletion of Pex3 reveals essential roles of PEX3-dependent peroxisomes in spermiogenesis

The Journal of Biomedical Research 2024年第1期38卷 24-36页

作者： Yejin Yao Baolu Shi Xiangzheng Zhang Xin Wang Shuangyue Li Ying Yao Yueshuai Guo Dingdong Chen Bing Wang Yan Yuan Jiahao Sha Xuejiang Guo State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical UniversityNanjingJiangsu 211166China Reproductive and Genetic Branch the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui 230001China State Key Laboratory of Reproductive Medicine and Offspring Health Women's Hospital of Nanjing Medical UniversityNanjing Maternity and Child Health Care HospitalNanjing Medical UniversityNanjingJiangsu 211166China.

peroxisomes are organelles enclosed by a single membrane and are present in various species.The abruption of peroxisomes is correlated with peroxisome biogenesis disorders and single peroxisomal enzyme deficiencies that induce diverse diseases in different organs.However,little is known about the protein compositions and corresponding roles of heterogeneous peroxisomes in various organs.Through transcriptomic and proteomic analyses,we observed heterogenous peroxisomal components among different organs,as well as between testicular somatic cells and different developmental stages of germ cells.As Pex3 is expressed in both germ cells and Sertoli cells,we generated Pex3 germ cell-and Sertoli cell-specific knockout mice.While Pex3 deletion in Sertoli cells did not affect spermatogenesis,the deletion in germ cells resulted in male sterility,manifested as the destruction of intercellular bridges between spermatids and the formation of multinucleated giant cells.Proteomic analysis of the Pex3-deleted spermatids revealed defective expressions of peroxisomal proteins and spermiogenesis-related proteins.These findings provide new insights that PEX3-dependent peroxisomes are essential for germ cells undergoing spermiogenesis,but not for Sertoli cells.

关键词： male infertility spermiogenesis peroxisome oxidative stress PEX3

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Transcriptomic profiling of peroxisome-related genes reveals a novel prognostic signature in hepatocellular carcinoma

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Genes & Diseases 2022年第1期9卷 116-127页

作者： Liewang Qiu Ke Zhan Kija Malale Xiaoling Wu Zhechuan Mei Department of Gastroenterology Yongchuan Hospital of Chongqing Medical UniversityChongqing 402160PR China Department of Gastroenterology The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400010PR China

Emerging evidence suggests that peroxisomes play a role in the regulation of tumorigenesis and cancer progression.However,the prognostic value of peroxisome-related genes has been rarely investigated.This study aimed to establish a peroxisome-related gene signature for overall survival(OS)prediction in patients with hepatocellular carcinoma(HCC).First,univariate Cox regression analysis was employed to identify prognostic peroxisome-related genes in The Cancer Genome Atlas liver cancer cohort,and least absolute shrinkage and selection operator Cox regression analysis was used to construct a 10-gene signature.The risk score based on the signature was positively correlated with poor prognosis(HR=4.501,95%CI=3.021–6.705,P=1.39e−13).Second,multivariate Cox regression incorporating additional characteristics revealed that the signature was an independent predictor.Time-dependent ROC curves demonstrated good performance of the signature in predicting the OS of HCC patients.The prognostic performance was validated using International Cancer Genome Consortium HCC cohort data.Gene set enrichment analysis revealed that the signature-related alterations in biological processes mainly involved peroxisomal functions.Finally,we developed a nomogram model based on the gene signature and TNM stage,which showed a superior prognostic power(C-index=0.702).Thus,our study revealed a novel peroxisome-related gene signature that may help improve personalized OS prediction in HCC patients.

关键词： Gene signature Hepatocellular carcinoma Nomogram peroxisome Prognosis

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Characterization of laccase gene StLAC6 and its involvement in the pathogenicity and peroxisome function in Setosphaeria turcica

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Journal of Integrative Agriculture 2022年第7期21卷 2019-2030页

作者： LIU Ning ZHANG Qian-qian JIA Hui ZHAO Bin ZHU Zi-ping CAO Zhi-yan DONG Jin-gao State Key Laboratory of North China Crop Improvement and Regulation/Key Laboratory of Hebei Province for Plant Physiology and Molecular Pathology Baoding 071001P.R.China College of Plant Protection Hebei Agricultural UniversityBaoding 071001P.R.China College of Life Sciences Hebei Agricultural UniversityBaoding 071001P.R.China Langfang Academy of Agriculture and Forestry Science Langfang 065000P.R.China

Laccases, as a kind of multicopper oxidase, play an important role in pigment synthesis and growth in fungi and are involved in their interactions with host plants. In Setosphaeria turcica, 9 laccase-like multicopper oxidases have been identified, and StLAC2 is involved in the synthesis of the melanin that accumulates in the cell wall. The function of another major laccase gene, StLAC6, was studied here. The knockout of StLAC6 had no effect on the growth, morphology or invasion ability of S. turcica, but the morphology and function of peroxisomes of knockout mutants were abnormal. The knockout of the StLAC6 gene resulted in increased contents of phenolic compounds and melanin and the sensitivity to fungicides increased compared with wild type strains. In the mutants of StLAC6, there is a significant change of the expression levels of other laccase genes. This study provides a new insight into laccase functions and the relationship of the laccase gene family in plant pathogenic fungi.

关键词： Setosphaeria turcica laccase StLAC6 peroxisome fungicides

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Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases

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World Journal of Gastroenterology 2010年第46期16卷 5830-5837页

作者： Johannes W Rey Andrea Noetel Aline Hardt Ali Canbay Hakan Alakus Axel zur Hausen Hans Peter Dienes Uta Drebber Margarete Odenthal Institute for Pathology University Hospital of Freiburg Department of Gastroenterology and Hepatology University Hospital of Essen Department of General Visceral and Cancer SurgeryUniversity Hospital of Cologne

AIM:To test the occurrence of the Pro12Ala mutation of the peroxisome proliferator-activated receptor-γ (PPARγ)2-gene in patients with non-alcoholic fatty liver disease (NAFLD) or alcoholic fatty liver disease (AFLD).METHODS:DNA from a total of 622 specimens including 259 blood samples of healthy blood donors and 363 histologically categorized liver biopsies of patients with NAFLD (n=263) and AFLD (n=100) were analyzed by Real-time polymerase chain reaction using allele-specific probes.RESULTS:In the NAFLD and the AFLD collective,3% of the patients showed homozygous occurrence of the Ala12 PPARγ2-allele,differing from only 1.5% cases in the healthy population.In NAFLD patients,a high incidence of the Ala12 mutant was not associated with the progression of fatty liver disease.However,we observed a significantly higher risk (odds ratio=2.50,CI:1.05-5.90,P=0.028) in AFLD patients carrying the mutated Ala12 allele to develop inflammatory alterations.The linkage of the malfunctioning Ala12-positive PPARγ2 isoform to an increased risk in patients with AFLD to develop severe steatohepatitis and fibrosis indicates a more prominent anti-inflammatory impact of PPARγ2 in progression of AFLD than of NAFLD.CONCLUSION:In AFLD patients,the Pro12Ala single nuclear polymorphism should be studied more extensively in order to serve as a novel candidate in biomarker screening for improved prognosis.

关键词： Single nucleotide polymorphism peroxisome proliferator-activated receptor γ Non-alcoholic steatohepatitis Alcoholic steatohepatitis Inflammation Fibrosis Hepatitis Steatosis Steatohepatitis

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PEX16 contributions to peroxisome import and metabolism revealed by viable Arabidopsis pex16 mutants

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Journal of Integrative Plant Biology 2019年第7期61卷 853-870页

作者： Sarah E.Burkhart Roxanna J.Llinas Bonnie Bartel Department of BioSciences Rice University

peroxisomes rely on peroxins(PEX proteins) for biogenesis, importing membrane and matrix proteins, and fission. PEX16, which is implicated in peroxisomal membrane protein targeting and forming nascent peroxisomes from the endoplasmic reticulum(ER), is unusual among peroxins because it is inserted co-translationally into the ER and localizes to both ER and peroxisomal membranes. PEX16 mutations in humans, yeast, and plants confer some common peroxisomal defects; however, apparent functional differences have impeded the development of a unified model for PEX16 action. The only reported pex16 mutant in plants, the Arabidopsis shrunken seed1 mutant, is inviable,complicating analysis of PEX16 function after embryogenesis. Here, we characterized two viable Arabidopsis pex16 alleles that accumulate negligible PEX16 protein levels. Both mutants displayed impaired peroxisome function-slowed consumption of stored oil bodies, decreased import of matrix proteins, and increased peroxisome size. Moreover,one pex16 allele exhibited reduced growth that could be alleviated by an external fixed carbon source, decreased responsiveness to peroxisomally processed hormone precursors, and worsened or improved peroxisome function in combination with other pex mutants. Because the mutations impact different regions of the PEX16 gene, these viable pex16 alleles allow assessment of the importance of Arabidopsis PEX16 and its functional domains.

关键词： pex16 mutants peroxisome metabolism

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Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI（4,5）P2 and extended synaptotagmins

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Science China(Life Sciences) 2019年第9期62卷 1117-1135页

作者： Jian Xiao Jie Luo Ao Hu Ting Xiao Meixin Li Zekai Kong Luyi Jiang Zimu Zhou Yacheng Liao Chang Xie Beibei Chu Honghua Miao Boliang Li Xiongjie Shi Bao-Liang Song College of Life Sciences the Institute for Advanced StudiesWuhan UniversityWuhan 430072China State Key Laboratory of Molecular Biology Institute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China Shenzhen Institute of Wuhan University Shenzhen 518057China

Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.

关键词： peroxisome ER membrane contacts E-Syts PI(4,5)P2

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Correlation of serum vitamin D, adipose tissue vitamin D receptor, and peroxisome proliferator-activated receptor γ in women with gestational diabetes mellitus

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Chinese Medical Journal 2019年第21期132卷 2612-2620页

作者： Hui-Yan Wang Guang-Tong She Li-Zhou Sun Hao Lu Yin-Pin Wang Jun Miao Ke-Zhuo Liu Cai-Feng Sun Hui-Hui Ju Department of Obstetrics The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210000China Department of Obstetrics Changzhou Woman and Children Health-Care Hospital Affiliated to Nanjing Medical UniversityChangzhouJiangsu 213003China.

Background:Gestational diabetes mellitus(GDM)is a common complication during pregnancy.Obesity and overweight are closely related to metabolic diseases and diabetes.However,the role of adipose tissue in the pathogenesis of GDM remains to be studied.The aim of this study was to investigate the correlation of vitamin D(VD)levels,VD receptor(VDR),and peroxisome proliferatoractivated receptor g(PPARg)expression with GDM in overweight or obese women.Methods:One hundred and forty pregnant women with full-term single-birth cesarean-section were selected as the study subjects and grouped(70 GDM women,including 35 non-overweight/non-obese women[group G1]and 35 women with overweight or obesity[group G2];70 pregnant women with normal glucose tolerance,including 35 non-overweight/non-obese women[group N1]and 35 overweight/obese women[group N2]).The levels of serum VD,blood biochemistry,and adiponectin were compared in these women.Subcutaneous adipose tissue was isolated from the abdominal wall incision.VDR and PPARg messenger RNA(mRNA)transcript levels in these adipose tissues were quantified by real-time polymerase chain reaction.The differences between the levels of PPARg protein and phosphorylated PPARg Ser273 were detected by Western blotting.Results:The serum VD level ofGDM women was lower in comparison to that of women with normal glucose tolerance(G1 vs.N1:20.62±7.87 ng/mL vs.25.85±7.29 ng/mL,G2 vs.N2:17.06±6.74 ng/mL vs.21.62±7.18 ng/mL,P<0.05),and the lowest in overweight/obese GDM women.VDR and PPARg mRNA expression was higher in the adipose tissues of GDM women in comparison to that of women with normal glucose tolerance(VDR mRNA:G1 vs.N1:210.00[90.58–311.46]vs.89.34[63.74–159.92],G2 vs.N2:298.67[170.84–451.25]vs.198.28[119.46–261.23],PPARg mRNA:G1 vs.N1:100.72[88.61–123.87]vs.87.52[66.37–100.04],G2 vs.N2:117.33[100.08–149.00]vs.89.90[76.95–109.09],P<0.05),and their expression was the highest in GDM+overweight/obese women.VDR mRNA levels positively correlated with the pre-pregnancy body mass index(BMI),pre-deliver

关键词： Gestational diabetes mellitus Overweight Obesity Serum vitamin D Vitamin D receptor peroxisome proliferatoractivated receptor gamma

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Effect of insulin and metformin on methylation and glycolipid metabolism of peroxisome proliferator-activated receptor γcoactivator-1A of rat offspring with gestational diabetes mellitus

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Asian Pacific Journal of Tropical Medicine 2016年第1期9卷 89-93页

作者： Ai-Qin Song Li-Rong Sun Yan-Xia Zhao Yan-Hua Gao Lei Chen Department of Pediatric Hematology Affiliated Hospital of Qingdao University

Objective:To discuss the effect of insulin and metformin on amethylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A(PPARGC1A) of rat offspring with gestational diabetes mellitus(GDM).Methods:A total of 45 pregnant rats received the intraperitoneal injection of streptozotocin to establish the pregnant rat model of GDM.A total of 21 pregnant rats with GDM were randomly divided into three groups,with 7ruts in each group,namely the insulin group,metformin group and control group.Rats in the insulin group received the abdominal subcutaneous injection of 1 mL/kg recombinant insulin glargine at 18:00 every day.Rats in the metformin group received the intragastric infusion of metformin hydrochloride at 18:00 every day,with the first dose of 300 mg/kg.The doses of two groups were adjusted every 3 d to maintain the blood glucose level at 2.65-7.62 mmol/L.Rats in the control group received the intragastric infusion of 1 mL normal saline at 18:00 every day.After the natural delivery of pregnant rats.10 offspring rats were randomly selected from each group.At birth,4 wk and 8 wk after the birth of offspring rats,the weight of offspring rats was measured.The blood glucose level of offspring rats was measured at 4wk and 8 wk,while the level of serum insulin,triglyceride and leptin was measured at 8 wk.Results:The weight of offspring rats at birth in the insulin group and metformin group was significantly lower than the one in the control group(P0.05).The fasting blood glucose and random blood glucose in the insulin group and metformin group at 4 wk and 8 wk were all significantly lower than ones in the control group(P0.05).The expression of PPARGC1 A mRNA in the insulin group and metformin group was significantly higher and the methylation level of PPARGC1 A was significantly lower than the one in the control

关键词： Insulin Metformin Gestational diabetes mellitus peroxisome proliferator-activated receptor γ coactivator-1 A Methylation Glycolipid metabolism

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Effect of Atorvastatin on Expression of peroxisome Proliferator-activated Receptor Beta/delta in Angiotensin Ⅱ-induced Hypertrophic Myocardial Cells In Vitro

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Chinese Medical Sciences Journal 2015年第4期30卷 245-251页

作者： Li Sheng Xu Yang Ping Ye Yong-xue Liu Chun-guang Han Department of Geriatric Cardiology Chinese PLA General Hospital Department of Pharmacology & Toxicology Beijing Institute of Radiation Medicine

Objective To explore the effect of atorvastatin on cardiac hypertrophy and to determine the potential mechanism involved. Methods An in vitro cardiomyocyte hypertrophy from neonatal rats was induced with angiotensinⅡ(Ang Ⅱ) stimulation. Before AngⅡ stimulation, the cultured rat cardiac myocytes were pretreated with atorvastatin at different concentrations(0.1, 1, and 10 μmol/L). The following parameters were evaluated: the myocyte surface area, 3H-leucine incorporation into myocytes, m RNA expressions of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase 9, matrix metalloproteinase 2, and interleukin-1β, m RNA and protein expressions of the δ/β peroxisome proliferator-activated receptor(PPAR) subtypes. Results It was shown that atorvastatin could ameliorate Ang Ⅱ-induced neonatal cardiomyocyte hypertrophy in the area of cardiomyocytes, 3H-leucine incorporation, and the expression of atrial natriuretic peptide and brain natriuretic peptide markedly. Meanwhile, atorvastatin also inhibited the augmented m RNA level of several cytokines in hypertrophic myocytes. Furthermore, the down-regulated expression of PPAR-δ/β at both the m RNA and protein levels in hypertrophic myocytes could be significantly reversed by atorvastatin treatment. Conclusions Atorvastatin could improve AngⅡ-induced cardiac hypertrophy and inhibit the expression of cytokines. Such effect might be partly achieved through activation of the PPAR-δ/β pathway.

关键词： peroxisome proliferator-activated receptor cardiac hypertrophy statin angiotensin Ⅱ

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Anluohuaxianwan Alleviates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats through Upregulation of peroxisome Proliferator-Activated Receptor-Gamma and Downregulation of Nuclear Factor-Kappa B/IκBα Signaling Pathway

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World Journal of Traditional Chinese Medicine 2019年第2期5卷 95-103页

作者： Lin Wang Wei Lu Yu-Hua Gao Hai-Jiang Yan Fei Pei Xue-En Liu Hui Zhuang Departments of Microbiology and Center of Infectious Diseases School of Basic Medical Sciences Peking University Health Science CenterBeijing Department of Clinical Laboratory The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Departments of Pathology School of Basic Medical SciencesPeking University Health Science CenterBeijing

Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.

关键词： Anluohuaxianwan,hepatic fibrosis,mechanism,nuclear factor-kappa B/IκBα, peroxisome proliferator-activated receptor-gamma

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