Molecular and Cellular Endocrinology最新文献_第8页

Oocyte-specific Ahr deletion disrupts folliculogenesis and female fertility in mice 卵母细胞特异性Ahr缺失破坏小鼠卵泡发生和雌性生育能力。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-11 DOI: 10.1016/j.mce.2025.112656

Pengtao Chen , Jinpeng Ruan , Fanzheng Xue , Xuejuan Dai , Chen Tang , Mingyue Chen , Nengming Xiao , Zhijian Cai , Chunyan Yang , Chengyong He , Wei Wang , Zhenghong Zuo

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies have shown that AHR plays a role in ovarian follicle development, the precise role of oocyte-expressed AHR in female reproduction remains unclear. In this study, oocyte-specific Ahr knockout (cKO) mice generated by crossing the Ahr ^flox/flox (Ahr ^fl/fl) and Gdf9-cre transgenic mouse strains were used to answer this open question. The cKO female mice exhibited a disrupted estrous cyclicity and subfertility. Histological analyses demonstrated that oocyte AHR loss reduces the number of primary follicles while increasing the number of secondary follicles and corpus lutea in mouse ovary. Hormonal analysis revealed decreased serum estradiol and follicle-stimulating hormone, indicating a disruption of the hypothalamic-pituitary-gonadal axis in cKO mice. TUNEL and Western blotting results demonstrate that deletion of oocyte AHR also results in increased apoptosis in ovarian granulosa cells (GCs), downregulated expression of Gdf9 and Bmp15 in oocytes, and disrupted bidirectional oocyte-GC communication. In conclusion, our findings reveal that the aryl hydrocarbon receptor plays a role beyond sensing environmental chemicals and endogenous compounds and underscore a critical role of oocyte-expressed Ahr in maintain follicle development, ovarian function, and female reproductive health.

芳烃受体（AHR）是一种配体激活的转录因子，调节多种生物过程，包括异种代谢、免疫反应和生殖。虽然先前的研究表明AHR在卵巢卵泡发育中起作用，但卵母细胞表达的AHR在女性生殖中的确切作用尚不清楚。本研究利用Ahrflox/flox （Ahrfl/fl）和Gdf9-cre转基因小鼠杂交产生的卵母细胞特异性Ahr敲除（cKO）小鼠来回答这个开放性问题。cKO雌性小鼠表现出发情周期中断和生育能力低下。组织学分析表明，卵母细胞AHR缺失减少了小鼠卵巢初级卵泡的数量，增加了次级卵泡和黄体的数量。激素分析显示血清雌二醇和促卵泡激素下降，表明cKO小鼠的下丘脑-垂体-性腺轴受到破坏。TUNEL和Western blotting结果表明，卵母细胞AHR的缺失也导致卵巢颗粒细胞（GCs）凋亡增加，下调卵母细胞Gdf9和Bmp15的表达，破坏卵母细胞与gc的双向通讯。总之，我们的研究结果揭示了芳烃受体在感知环境化学物质和内源性化合物之外的作用，并强调了卵母细胞表达的Ahr在维持卵泡发育、卵巢功能和女性生殖健康方面的关键作用。

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引用次数: 0

Developmental programming: Differing impact of prenatal testosterone and prenatal bisphenol-A -treatment on hepatic methylome in female sheep 发育规划：产前睾酮和产前双酚a处理对母羊肝脏甲基组的不同影响。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-04 DOI: 10.1016/j.mce.2025.112655

John Dou , Soundara Viveka Thangaraj , Yiran Zhou , Vasantha Padmanabhan , Kelly Bakulski

Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health. Using Suffolk sheep, the study involved two cohorts: one exposed to prenatal-T and the other to prenatal-BPA. Whole genome bisulfite sequencing was employed to map DNA methylation across over 22 million CpG sites. Regions with p-value<10⁻⁴ and a magnitude of difference of at least 5 % methylation between groups were considered differentially methylated. Results demonstrated substantial differential methylation in the liver tissues due to both treatments, with prenatal-T causing unique epigenetic modifications distinct from those induced by prenatal-BPA. Specifically, prenatal-T treatment resulted in 53 differentially methylated regions (DMRs), of which 31 were located in gene regions, including exons. Prenatal-BPA exposure led to 32 DMRs, with 22 associated with gene regions. These modifications were associated with genes governing lipid and glucose metabolism, potentially underlying the observed metabolic disruptions such as insulin resistance and dyslipidemia. Pathway analysis revealed that genes differentially methylated due to prenatal-T were involved in cellular organization, while those affected by prenatal-BPA were enriched in signal regulation pathways. The findings underscore how prenatal exposure to steroid excess and steroid-mimics influence epigenetic landscapes, contributing to metabolic disease programming.

类固醇激素是怀孕和胎儿发育不可或缺的一部分，调节代谢、炎症和免疫反应等过程。过量的产前类固醇暴露，通过生活方式选择或环境化学物质，可导致后代代谢功能障碍。这项研究的重点是暴露于睾酮(T)和双酚A （BPA）如何影响肝脏的DNA甲基组，甲基组是影响长期健康的表观基因组的关键组成部分。这项研究以萨福克羊为研究对象，分为两组：一组暴露于产前的t，另一组暴露于产前的bpa。亚硫酸氢盐全基因组测序用于绘制超过2200万个CpG位点的DNA甲基化图谱。p值为4且组间甲基化程度相差至少5%的区域被认为是差异甲基化。结果表明，由于两种治疗，肝脏组织中的甲基化存在显著差异，产前t引起的独特表观遗传修饰与产前bpa诱导的修饰不同。具体来说，产前t治疗导致53个差异甲基化区域（DMRs），其中31个位于基因区域，包括外显子。产前bpa暴露导致32例dmr，其中22例与基因区域有关。这些修饰与控制脂质和葡萄糖代谢的基因有关，可能是观察到的代谢中断（如胰岛素抵抗和血脂异常）的基础。通路分析显示，受产前t基因差异甲基化的基因参与细胞组织，而受产前bpa影响的基因则富集于信号调节通路。研究结果强调了产前暴露于类固醇过量和类固醇模拟物如何影响表观遗传景观，促进代谢疾病编程。

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引用次数: 0

RNA binding protein SERBP1 is indispensable for oocyte development and maturation in mice. RNA结合蛋白SERBP1是小鼠卵母细胞发育和成熟所必需的。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-01 DOI: 10.1016/j.mce.2025.112644

Lingjuan Wang, Sijin OuYang, Bin Li, Na Kong

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression and RNA processing during mammalian oocyte development. SERPINE1 mRNA-binding protein 1 (SERBP1), a conserved RNA-binding protein (RBP), exhibits prominent expression in the female reproductive system and throughout oogenesis. Conditional deletion of Serbp1 using oocyte-specific Zp3⁠/⁠Gdf9⁠-Cre drivers resulted in arrested oocyte growth, female infertility, and failure of blastocyst formation from two-cell embryos. Phenotypic analysis revealed spindle assembly defects, impaired asymmetric division, and compromised meiotic competence in oocytes. Notably, Serbp1 ablation also induced granulosa cell apoptosis and elevated Erk1/2 phosphorylation levels, indicating dysregulation of somatic microenvironment. Furthermore, conditional knockout mice exhibited prolonged diestrus cycles. Collectively, these findings demonstrate that SERBP1 coordinates essential RNA-regulatory functions for oocyte developmental competence through both cell-autonomous mechanisms and somatic-germline crosstalk.

RNA结合蛋白（rbp）是哺乳动物卵母细胞发育过程中转录后基因表达和RNA加工的关键调控因子。SERPINE1 mrna结合蛋白1 （SERBP1）是一种保守的rna结合蛋白（RBP），在雌性生殖系统和整个卵发生过程中均有显著表达。使用卵母细胞特异性Zp3 / Gdf9 -Cre驱动因子条件删除Serbp1导致卵母细胞生长受阻、女性不育和两细胞胚胎囊胚形成失败。表型分析显示纺锤体组装缺陷，不对称分裂受损，卵母细胞减数分裂能力受损。值得注意的是，Serbp1消融还引起颗粒细胞凋亡和Erk1/2磷酸化水平升高，表明体细胞微环境失调。此外，条件敲除小鼠表现出延长的死亡周期。总之，这些发现表明SERBP1通过细胞自主机制和体细胞-种系串扰协调卵母细胞发育能力的基本rna调控功能。

引用次数: 0

The N-terminal region of HASPIN regulates phosphorylation of AURKA and meiotic progression in spermatocytes HASPIN的n端区域调节AURKA的磷酸化和精母细胞的减数分裂进程

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-28 DOI: 10.1016/j.mce.2025.112645

Haojie Li , Yaoting Xu , Xinyi Jiang , Jie Ren , Yulian Wang , Xiangzheng Zhang , Mengmeng Gao , Longsheng Zhang , Yue Wang , Zongze Li , Suwei Wang , Tianye Wang , Mengyi Wang , Chenghao Situ , Xuejiang Guo , Hui Zhu

Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this study, we found that the intrinsically disordered N-terminal domain of HASPIN is also required for this function. Mice with deletion of N-terminal amino acids (aa) 1-243 of HASPIN exhibited reduced testicular size, sperm count, and fertility. Using immunoprecipitation-mass spectrometry and phosphoproteomics analysis, we found that HASPIN could interact with AURKA and regulate its phosphorylation at T279 via its N-terminus. Taken together, our results suggest that the N-terminus of HASPIN regulates AURKA kinase activity to affect male fertility.

蛋白磷酸化是一个重要的翻译后修饰，在减数分裂中起着关键的调节作用。HASPIN是一种从酵母到哺乳动物都高度保守的激酶，是男性生育所必需的。在本研究中，我们发现HASPIN的内在无序n端结构域也是该功能所必需的。缺失HASPIN n端氨基酸（aa） 1-243的小鼠睾丸大小、精子数量和生育能力均下降。通过免疫沉淀-质谱和磷酸化蛋白质组学分析，我们发现HASPIN可以与AURKA相互作用，并通过其n端调控其T279位点的磷酸化。综上所述，我们的研究结果表明，HASPIN的n端调控AURKA激酶活性，影响男性生育能力。

引用次数: 0

α-Linolenic acid rich-chia seed improves glucose tolerance, modulates gluconeogenic pathway and hepatic insulin signaling in an experimental model of metabolic syndrome 富含α-亚麻酸的奇亚籽改善糖耐量，调节糖异生途径和肝脏胰岛素信号通路

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-20 DOI: 10.1016/j.mce.2025.112643

Michelle Berenice Vega Joubert , María Eugenia Oliva , Paola Ingaramo , María Eugenia D'Alessandro

Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as the hepatic manifestation of Metabolic Syndrome. The aim of this work was to evaluate the effects of chia seed, rich in α-linolenic acid, on glucose tolerance, enzyme activities and transcription factors involved in gluconeogenesis, and key molecules in insulin signaling in sucrose-rich diet (SRD) fed rats. Male Wistar rats were fed a reference diet (RD) for 6 months or a SRD for 3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving SRD for up to 6 months and the other was fed with a SRD where chia seed was incorporated as a source of dietary fat for the next 3 months (SRD + CHIA). The results showed that chia seed improved glucose tolerance, reversed the increase in PEPCK, FBPase, and Glucose-6-Pase, and reduced the Glucose-6-Pase/GK ratio. Additionally, chia seed improved tAMPK and pAMPK protein levels, while maintaining GLUT-2 protein levels similar to those in the RD group. Under insulin stimulation, p-AKT protein levels were higher in the SRD + CHIA group than in the unstimulated group. IRS-1 and PGC-1α protein expression levels were similar among the three experimental groups. Liver FOXO-1 mRNA expression was decreased in the SRD + CHIA group. Finally, chia seed increased the n-3/n-6 ratio in hepatic membrane phospholipids. The present study demonstrated that chia seed modulate multiple mechanisms that enhance glucose metabolism and insulin signaling in SRD fed rats. These effects are mediated, at least in part, by the enrichment of n-3 PUFAs in liver tissue.

代谢功能障碍相关脂肪变性肝病（MASLD）是公认的代谢综合征的肝脏表现。本研究旨在探讨富含α-亚麻酸的奇亚籽对富蔗糖日粮大鼠糖耐量、糖异生相关酶活性、转录因子及胰岛素信号通路关键分子的影响。雄性Wistar大鼠饲喂参考日粮（RD） 6个月，SRD饲喂3个月。后一组随机分为两个亚组。一个亚组继续接受SRD长达6个月，另一个亚组在接下来的3个月里，在SRD中加入奇亚籽作为膳食脂肪的来源（SRD + chia）。结果表明，奇亚籽改善了葡萄糖耐量，逆转了PEPCK、FBPase和glucose -6- pase的升高，降低了glucose -6- pase /GK比值。此外，奇亚籽提高了tAMPK和pAMPK蛋白水平，同时维持了与RD组相似的GLUT-2蛋白水平。胰岛素刺激下，SRD + CHIA组p-AKT蛋白水平高于未刺激组。3个实验组中IRS-1和PGC-1α蛋白表达水平相似。SRD + CHIA组肝脏FOXO-1 mRNA表达降低。最后，奇亚籽提高了肝膜磷脂的n-3/n-6比值。本研究表明，奇亚籽可通过多种机制调节SRD喂养大鼠的葡萄糖代谢和胰岛素信号。这些作用至少部分是由肝组织中n-3 PUFAs的富集介导的。

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引用次数: 0

Transcriptomic modifications in maternal pancreatic islets during the period around weaning in mice 小鼠断奶前后母体胰岛的转录组修饰。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-12 DOI: 10.1016/j.mce.2025.112642

Xadeni Burgos-Gamez , Paulina Morales-Castillo , Alain Hernández-Vázquez , Karina Pastén-Hidalgo , Francisco García-Vázquez , Cristina Fernandez-Mejia

Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an increase in beta-cell proliferation and a significant islet expansion around the weaning period in mice. This study aims to identify transcripts associated with changes in the islets around weaning—a physiological stage previously unexplored in islets. A ribonucleic acid (RNA) sequencing analysis of the transcriptome was performed at four key time points: the end of lactation, when beta-cell proliferation increases; the day of weaning, when the hormonal and metabolic environment transitions from lactation to the non-lactating stage; the third day post-weaning, when islet area peaks, as observed in our prior studies; and in age-matched female control mice. The results revealed dynamic transcriptomic changes. The messenger ribonucleic acid (mRNA) expression levels of genes regulated by prolactin, including its receptor, signaling inhibitor Cish, tryptophan hydroxylase, and osteoprotegerin, increased during lactation and subsequently declined. Plasma prolactin concentrations rose during lactation, but plasma osteoprotegerin levels remained stable across groups. Notably, no changes were observed in known prolactin-regulated cyclins that positively influence the cell cycle, such as Ccna2, Ccnb1, and Ccnb2. However, a decrease in the expression of Cdkn1a, a negative regulator of the cell cycle, was noted. Surprisingly, microscopy analysis indicated increased apoptosis markers in islet peripheral cells that were negative for insulin immunostaining. This study is the first to identify transcriptomic and cellular changes around weaning, offering new insights into islet mass plasticity.

确定增强β细胞质量的机制和分子因素对于制定对抗糖尿病的策略至关重要，因为β细胞质量随着疾病进展而下降。最近的研究表明，在小鼠断奶期间，β细胞增殖增加，胰岛显著扩张。本研究旨在确定与断奶前后胰岛变化相关的转录本，这是一个以前未在胰岛中探索过的生理阶段。在四个关键时间点对转录组进行核糖核酸（RNA）测序分析：哺乳结束时，β细胞增殖增加；断奶当天，激素和代谢环境从泌乳阶段过渡到非泌乳阶段；断奶后第三天，胰岛面积达到峰值，与我们之前的研究结果一致；在年龄匹配的雌性对照小鼠中。结果显示动态转录组变化。泌乳素调节基因的信使核糖核酸（mRNA）表达水平，包括其受体、信号抑制剂Cish、色氨酸羟化酶和骨保护素，在泌乳期间升高，随后下降。血浆催乳素浓度在哺乳期升高，但血浆骨保护素水平在各组间保持稳定。值得注意的是，未观察到已知的催乳素调节的细胞周期蛋白（如Ccna2、Ccnb1和Ccnb2）的变化。然而，Cdkn1a（细胞周期的负调节因子）的表达减少被注意到。令人惊讶的是，显微镜分析显示胰岛素免疫染色阴性的胰岛外周细胞凋亡标志物增加。这项研究首次确定了断奶前后的转录组学和细胞变化，为胰岛质量可塑性提供了新的见解。

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引用次数: 0

MeCP2 attenuates inflammation and regulates T cell phenotype via SFRP4 suppression in preeclampsia MeCP2在子痫前期通过抑制SFRP4减轻炎症并调节T细胞表型。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-06 DOI: 10.1016/j.mce.2025.112637

Mei Peng , Yanting Nie , Ying Luo, Grace Divine Milebe Nkoua, Shaohan Zhang, Hongyu Liu, Wen Zhang, Songyuan Xiao, Yang Zhou, Weisi Lai, Yali Deng, Ling Yu, Jinyu Liu, Xihong Zhou, Yiling Ding

Preeclampsia (PE) is a major pregnancy complication characterized by an aberrant immune response. Methyl CpG binding protein 2 (MeCP2) is a potential regulator of secreted frizzled-related protein 4 (SFRP4), and both MeCP2 and SFRP4 are implicated in immune homeostasis. This study investigated the regulatory role of MeCP2/SFRP4 in immune cells in PE. A rat model of PE induced by reduced uterine perfusion pressure (RUPP) and an in vitro model using lipopolysaccharide (LPS)-stimulated HTR-8/SVneo cells were established. A co-culture system of LPS-challenged HTR-8/SVneo cells and T cells was also employed. MeCP2 expression was reduced and inversely correlated with SFRP4 levels in PE. MeCP2 overexpression suppressed Th1/Th17 differentiation while promoting Th2/Treg phenotypes, along with modulation of associated immune cytokines. It also enhanced colony formation, proliferation, migration, and invasion, while reducing apoptosis following co-culture. SFRP4 supplementation reversed the effects of MeCP2 overexpression on T cell proliferation and cytokine release. Collectively, these findings suggest that MeCP2 regulates T cell phenotype and inflammatory responses by inhibiting SFRP4, providing potential avenues for immunotherapeutic intervention in PE.

子痫前期（PE）是一个主要的妊娠并发症的特点是异常的免疫反应。甲基CpG结合蛋白2 （MeCP2）是分泌卷曲相关蛋白4 （SFRP4）的潜在调节因子，MeCP2和SFRP4都与免疫稳态有关。本研究探讨了MeCP2/SFRP4在PE免疫细胞中的调节作用。建立子宫灌注压降低（RUPP）诱导大鼠PE模型和脂多糖（LPS）刺激HTR-8/SVneo细胞体外模型。采用lps攻毒HTR-8/SVneo细胞与T细胞共培养体系。PE中MeCP2表达降低，且与SFRP4水平呈负相关。MeCP2过表达抑制Th1/Th17分化，同时促进Th2/Treg表型，以及相关免疫细胞因子的调节。它还能促进菌落的形成、增殖、迁移和侵袭，同时减少共培养后的细胞凋亡。补充SFRP4逆转了MeCP2过表达对T细胞增殖和细胞因子释放的影响。总之，这些发现表明MeCP2通过抑制SFRP4调节T细胞表型和炎症反应，为PE的免疫治疗干预提供了潜在的途径。

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引用次数: 0

Adipose tissue-specific Yap knockout exacerbates diet-induced obesity through suppression of lipolysis 脂肪组织特异性Yap基因敲除通过抑制脂肪分解加剧饮食诱导的肥胖。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-06 DOI: 10.1016/j.mce.2025.112631

Huabing Xiao , Ping Jiang , Fan Xia , Dayu Wu , Hui Huang , Sihui Tu , Huilan Luo , Yiling Wu , Qiong Duan , Lingyan Zhu

Background and aims

YAP regulates various cellular processes, including cell contact inhibition, mechanotransduction, cell differentiation and proliferation, apoptosis, and cancer progression. Although YAP suppresses adipogenesis in vitro, its role in obesity has not yet been completely elucidated.

Methods and results

In this study, we generated an adipose tissue-specific Yap knockout mouse model (YapaKO), and found that male, but not female, YapaKO mice showed an enhanced high-fat diet-induced obesity phenotype compared to control mice. Mechanistically, this effect is potentially due to suppressed lipolytic activity, which results from the decreased expression of triglyceride lipolytic enzymes, including ATGL and HSL. The inhibition of lipolytic activity led to reduced levels of circulating free fatty acids during fasting, making male mice unable to maintain core body temperature after cold exposure and showing impaired exercise capability in the fasted state. This study reveals a novel role of YAP in controlling lipolysis.

Conclusion

YAP is a physiological regulator of lipolysis in the adipose tissue. YAP activation in adipose tissue may facilitate lipolysis and reduce obesity.

背景和目的：YAP调节多种细胞过程，包括细胞接触抑制、机械转导、细胞分化和增殖、细胞凋亡和癌症进展。虽然YAP在体外抑制脂肪形成，但其在肥胖中的作用尚未完全阐明。方法和结果：在本研究中，我们建立了脂肪组织特异性YapaKO敲除小鼠模型（YapaKO），发现与对照小鼠相比，雄性（而非雌性）YapaKO小鼠表现出更高的高脂肪饮食诱导的肥胖表型。从机制上讲，这种影响可能是由于抑制了脂溶活性，这是由甘油三酯脂溶酶（包括ATGL和HSL）的表达减少引起的。抑制脂溶活性导致禁食期间循环游离脂肪酸水平降低，使雄性小鼠在冷暴露后无法维持核心体温，并在禁食状态下表现出运动能力受损。本研究揭示了YAP在控制脂肪分解中的新作用。结论：YAP是脂肪组织中脂肪分解的生理调节剂。在脂肪组织中激活YAP可能促进脂肪分解和减少肥胖。

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引用次数: 0

Epigenetic regulation of sex: the role of DNA methylation and zbtb38 in zebrafish sex differentiation and heat-induced masculinization 性别的表观遗传调控：DNA甲基化和zbtb38在斑马鱼性别分化和热诱导雄性化中的作用。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-05 DOI: 10.1016/j.mce.2025.112636

Fabien Pierron, Débora Heroin, Flore Daramy

There is increasing evidence that global change can threaten biodiversity by inducing skewed sex ratios. Accumulating evidences support a role of epigenetics, mainly DNA methylation, in sex differentiation. The aim of the present work was to investigate the potential role of zbtb38, a transcriptional factor that binds to methylated promoters, in sex differentiation and/or maintenance in zebrafish. We analyzed the methylation and transcription level of zbtb38 in males, females and undifferentiated individuals raised at standard or high temperature, a masculinizing factor. Results were compared to those obtained for genes already known to be involved in sex differentiation/maintenance (cyp19a1a, foxl2a, dmrt1). All genes presented a sex-specific pattern of DNA methylation and transcription but the most significant differences between sexes were observed for zbtb38. Moreover, a highly significant positive correlation was observed between the methylation level of zbtb38 and cyp19a1a, which encodes an enzyme that converts androgens into estradiol. However, while the hypermethylation of cyp19a1a was associated with its down-regulation, an inverse relationship was observed for zbtb38, providing a basis for mutual antagonism. Furthermore, zbtb38 was the only gene for which its transcription level was affected by temperature, being up-regulated in females that escaped to masculinization. Finally, despite embryos presented a paternal methylome, zbtb38 was the only gene for which its methylation level rapidly changed during early development to reach intermediate values between males and females at the larval stage, ie a bi-potential state. Our results strongly support a strategic role of DNA methylation and zbtb38 in sex differentiation and maintenance.

越来越多的证据表明，全球变化会导致性别比例失衡，从而威胁到生物多样性。越来越多的证据支持表观遗传学，主要是DNA甲基化，在性别分化中的作用。zbtb38是一种结合甲基化启动子的转录因子，其在斑马鱼性别分化和/或维持中的潜在作用。我们分析了zbtb38在雄性、雌性和未分化个体中甲基化和转录水平。结果与已知参与性别分化/维持的基因（cyp19a1a, foxl2a, dmrt1）的结果进行了比较。所有基因的DNA甲基化和转录都呈现出性别特异性模式，但zbtb38的性别差异最为显著。此外，zbtb38的甲基化水平与cyp19a1a之间存在高度显著的正相关，cyp19a1a编码一种将雄激素转化为雌二醇的酶。然而，cyp19a1a的高甲基化与其下调相关，而zbtb38则相反，这为相互拮抗提供了基础。此外，zbtb38是唯一一个转录水平受温度影响的基因，在雌性逃向雄性化的过程中被上调。最后，尽管胚胎存在父系甲基化组，但zbtb38是唯一在早期发育过程中甲基化水平迅速变化的基因，在幼虫期达到雄性和雌性之间的中间值，即双电位状态。我们的研究结果有力地支持了DNA甲基化和zbtb38在性别分化和维持中的战略性作用。

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引用次数: 0

Pirin knockdown alleviates the progression of metabolic dysfunction-associated steatotic liver disease by inhibiting hepatic lipid deposition, inflammation, and fibrosis Pirin敲低可通过抑制肝脏脂质沉积、炎症和纤维化来减轻代谢功能障碍相关脂肪变性肝病的进展。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-08-05 DOI: 10.1016/j.mce.2025.112632

Yujing Wang , Yuanxin Xu , Yilin Liu , Jindan Lin , Xincai Hong , Shuang Yan

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global disease with a broad spectrum of symptoms. Pirin (PIR) is involved in a variety of biological and molecular processes. However, the role of PIR in MASLD remains unclear. Rats were fed with high-fat and high-cholesterol (HFC) diet to induce MASLD. Time-course results showed that liver in HFC-fed rats exhibited a progressive increase in hepatic tissue damage over time (3, 6, and 9 weeks), and developed in obvious hepatic fibrosis and steatosis at week 9. Meanwhile, HFC feeding also gradually increased PIR expression in liver. In vitro, PIR expression was up-regulated in palmitic acid (PA)-induced Hep3B cells. PIR knockdown using PIR shRNA plasmid inhibited steatosis and expression of ACLY, FASN, and XBP1 in PA-induced Hep3B cells. Knocking down PIR inhibited hepatocyte inflammation by inhibiting phosphor-NF-κB p65 into the nucleus, which inhibited the expression of TNF-α and IL-1β. In MASLD, hepatocyte inflammation activates hepatic stellate cell, thereby leading to hepatic fibrosis. Supernatant from PA-treated Hep3B with PIR knockdown inhibited LX-2 activation, as evidenced by decreased expression of Col1A1 and α-SMA in LX-2 cells. Together, these results suggested that PIR knockdown might alleviate the progression of MASLD by inhibiting liver lipid deposition and inflammation, further inhibiting liver fibrosis. Transcriptome data analysis suggested that alteration in the expression of lipid metabolism-related pathways and genes might be a potential cause of PIR regulation in MASLD progression. These findings may reveal a novel target for MASLD therapy.

代谢功能障碍相关脂肪变性肝病（MASLD）是一种具有广泛症状的全球性疾病。Pirin （PIR）参与多种生物和分子过程。然而，PIR在MASLD中的作用仍不清楚。采用高脂高胆固醇（HFC）饲料诱导大鼠MASLD。时间过程结果显示，随着时间的推移（3,6和9周），hfc喂养大鼠肝脏的肝组织损伤逐渐增加，并在第9周出现明显的肝纤维化和脂肪变性。同时，HFC喂养也逐渐增加肝脏中PIR的表达。在体外，棕榈酸（PA）诱导的Hep3B细胞中PIR表达上调。在pa诱导的Hep3B细胞中，使用PIR shRNA质粒敲除PIR可抑制脂肪变性和ACLY、FASN和XBP1的表达。下调PIR通过抑制磷酸化nf -κB p65进入细胞核，抑制TNF-α和IL-1β的表达，从而抑制肝细胞炎症。在MASLD中，肝细胞炎症激活肝星状细胞，从而导致肝纤维化。PIR敲低pa处理Hep3B的上清液抑制LX-2的活化，LX-2细胞中Col1A1和α-SMA的表达降低。综上所述，这些结果表明PIR敲低可能通过抑制肝脏脂质沉积和炎症来缓解MASLD的进展，从而进一步抑制肝纤维化。转录组数据分析表明，脂质代谢相关通路和基因表达的改变可能是PIR调节MASLD进展的潜在原因。这些发现可能揭示了MASLD治疗的新靶点。

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