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Clinical impact of the TPM1 p.Tyr221Cys variant causing hypertrophic cardiomyopathy TPM1 p.Tyr221Cys变异引起肥厚性心肌病的临床影响
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-26 DOI: 10.1016/j.gendis.2025.101575
Alessio Marinelli , Giuliana Longo , Vincenzo Cirigliano , Esther Campopiano , Clementina Dugo , Luca Ghiselli , Andrea Chiampan , Gianluca Ferri , Alessandro Costa , Stefano Bonapace , Laura Lanzoni , Giulio Molon
{"title":"Clinical impact of the TPM1 p.Tyr221Cys variant causing hypertrophic cardiomyopathy","authors":"Alessio Marinelli , Giuliana Longo , Vincenzo Cirigliano , Esther Campopiano , Clementina Dugo , Luca Ghiselli , Andrea Chiampan , Gianluca Ferri , Alessandro Costa , Stefano Bonapace , Laura Lanzoni , Giulio Molon","doi":"10.1016/j.gendis.2025.101575","DOIUrl":"10.1016/j.gendis.2025.101575","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101575"},"PeriodicalIF":6.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
New genetic insights into HIV-associated neurocognitive disorder and Alzheimer's disease hiv相关神经认知障碍和阿尔茨海默病的新遗传见解
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-26 DOI: 10.1016/j.gendis.2025.101576
Hai Duc Nguyen , Woong-Ki Kim
{"title":"New genetic insights into HIV-associated neurocognitive disorder and Alzheimer's disease","authors":"Hai Duc Nguyen , Woong-Ki Kim","doi":"10.1016/j.gendis.2025.101576","DOIUrl":"10.1016/j.gendis.2025.101576","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101576"},"PeriodicalIF":6.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-cell transcriptome analysis of in vivo and in vitro human pancreas development 体内和体外人胰腺发育的单细胞转录组分析
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-25 DOI: 10.1016/j.gendis.2025.101573
Xiaofei Zhang , Hongyan Yi , Zhuo Ma , Yinsuo Zhao , Yanlin Ma , Eli Song , Tao Xu
{"title":"Single-cell transcriptome analysis of in vivo and in vitro human pancreas development","authors":"Xiaofei Zhang , Hongyan Yi , Zhuo Ma , Yinsuo Zhao , Yanlin Ma , Eli Song , Tao Xu","doi":"10.1016/j.gendis.2025.101573","DOIUrl":"10.1016/j.gendis.2025.101573","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 6","pages":"Article 101573"},"PeriodicalIF":6.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2 外源性丙酮酸通过靶向胞质磷脂酶A2治疗结肠炎
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-22 DOI: 10.1016/j.gendis.2025.101571
Sadaf Hasan , Nabil Ghani , Xiangli Zhao , Julia Good , Chuan-ju Liu
{"title":"Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2","authors":"Sadaf Hasan ,&nbsp;Nabil Ghani ,&nbsp;Xiangli Zhao ,&nbsp;Julia Good ,&nbsp;Chuan-ju Liu","doi":"10.1016/j.gendis.2025.101571","DOIUrl":"10.1016/j.gendis.2025.101571","url":null,"abstract":"<div><div>Ulcerative colitis is an idiopathic, chronic inflammatory bowel disease. Its pathogenesis is multifactorial involving inflammation and immune dysregulation. Proinflammatory TNFα/NFκB signaling is believed to play a cardinal role in ulcerative colitis. Growing evidence indicates the molecular interactions between the cellular metabolites and different phases of inflammation. This study aims to identify the metabolites that can inhibit TNFα/NFκB signaling and are potentially therapeutic against various TNFα-associated inflammatory diseases, particularly inflammatory bowel diseases. We performed <em>in vitro</em> and <em>in vivo</em> screening of cellular metabolites to inhibit TNFα/NFκB signaling. Multiple confirmation assays, including NFκB translocation, quantitative real-time PCR, ELISA, immunofluorescence staining, and RNA sequencing analysis were executed. Drug affinity-responsive target stability assay with proteomics was utilized for target identification. cPLA2 ablated mice with dextran sodium sulfate-induced colitis were employed to assess pyruvate's dependence on its molecular target in attenuating ulcerative colitis pathogenesis. Metabolite screening and subsequent validation with multiple approaches led to the isolation of pyruvate, a glycolytic metabolite, and a critical node in several metabolic pathways, as a novel inhibitor of TNFα/NFκB signaling. Importantly, pyruvate suppressed inflammation, preserved colonic histology, maintained tight junction proteins, and regulated permeability in the ulcerative colitis model. Additionally, cPLA2 was identified as a previously unknown target of pyruvate and pyruvate largely lost its therapeutic effects against ulcerative colitis in cPLA2-deficient mice. Conclusively, this study not only unveils pyruvate as an antagonist of TNFα/NFκB signaling and therapeutic intervention against colitis but also provides mechanistic insight into the mode of action of pyruvate.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101571"},"PeriodicalIF":6.9,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway PDE4DIP功能障碍通过Rho-ROCK通路调节细胞极性、骨架和能量代谢,参与LVNC的发展
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-21 DOI: 10.1016/j.gendis.2025.101568
Wuxia Gu , Hongyan Li , Wenjing Yuan , Xiaoqiong Fu , Rui Wang , Xiaohui Xu , Xuemei Liao , LingJuan Liu , Bo Pan , Jie Tian , Haixin Yuan , Yi Huang , Tiewei Lu
{"title":"Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway","authors":"Wuxia Gu ,&nbsp;Hongyan Li ,&nbsp;Wenjing Yuan ,&nbsp;Xiaoqiong Fu ,&nbsp;Rui Wang ,&nbsp;Xiaohui Xu ,&nbsp;Xuemei Liao ,&nbsp;LingJuan Liu ,&nbsp;Bo Pan ,&nbsp;Jie Tian ,&nbsp;Haixin Yuan ,&nbsp;Yi Huang ,&nbsp;Tiewei Lu","doi":"10.1016/j.gendis.2025.101568","DOIUrl":"10.1016/j.gendis.2025.101568","url":null,"abstract":"<div><div>Left ventricular non-compaction (LVNC), is a hereditary cardiomyopathy with limited treatments. Our previous study linked phosphodiesterase 4D interacting protein (PDE4DIP) to LVNC development. To explore the functional role of PDE4DIP activation in regulating cell polarity, skeleton, and energy metabolism, and to elucidate its mechanisms driving LVNC development, bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects. Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes, respectively. Electron microscopy, MitoTracker-Green staining, and an ATP kit were employed to assess mitochondria's morphology and functional status. Real-time quantitative PCR, western blotting, and immunofluorescence assays were employed to detect the expression of cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins. Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2, respectively. We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects. Furthermore, overexpression of PDE4DIP induced cytoskeletal disorganization, decreased ATP content and cell migration, and increased cell proliferation and mitochondrial vacuolation. Moreover, the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration. Mechanically, overexpression of PDE4DIP inhibited cell polarity-, skeleton-, and Rho-ROCK signaling-related genes and proteins, which could be increased by knockdown of PDE4DIP, suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway. This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity, skeleton, and energy metabolism through the Rho-ROCK pathway.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101568"},"PeriodicalIF":6.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The biological roles and molecular mechanisms of m6A reader IGF2BP1 in the hallmarks of cancer m6A读取器IGF2BP1在癌症标志中的生物学作用和分子机制
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-20 DOI: 10.1016/j.gendis.2025.101567
Li Qiu , Shourong Wu , Lei Zhang , Wenfang Li , Debing Xiang , Vivi Kasim
{"title":"The biological roles and molecular mechanisms of m6A reader IGF2BP1 in the hallmarks of cancer","authors":"Li Qiu ,&nbsp;Shourong Wu ,&nbsp;Lei Zhang ,&nbsp;Wenfang Li ,&nbsp;Debing Xiang ,&nbsp;Vivi Kasim","doi":"10.1016/j.gendis.2025.101567","DOIUrl":"10.1016/j.gendis.2025.101567","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) is the most abundant and well-investigated internal RNA modification in eukaryotic RNAs, affecting its target gene expression by controlling RNA localization, splicing, stability, and translation. m6A modifications are regulated by m6A methyltransferase complex, demethylase, and reading proteins. Insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins, has recently been identified as a vital m6A reading protein. IGF2BP1 is highly expressed in various tumors and is associated with poor prognosis and treatment resistance. Furthermore, previous studies have shown that IGF2BP1 plays critical roles in regulating various cancer hallmarks, including sustained cell proliferation, cell death resistance, activation of invasion and metastasis, deregulated cellular energetics, immune evasion, and unlocking phenotypic plasticity. IGF2BP1 could promote the expression of cancer-related genes by recognizing their m6A sites, thereby altering cell characteristics, and eventually, malignancy. Therefore, IGF2BP1 might be a potential target for tumor diagnosis and anti-tumor therapeutic strategies. This review summarizes the current knowledge on the functional roles and underlying molecular mechanisms of IGF2BP1 in regulating cancer hallmarks. Moreover, we discuss the prospects of IGF2BP1 as a potential tumor diagnosis marker, as well as a potential target for an anti-tumor therapeutic strategy.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101567"},"PeriodicalIF":6.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-omics analysis of epigenetic dysregulation reveals clinical heterogeneity and evaluates the immunotherapeutic potential of lung adenocarcinoma 表观遗传失调的多组学分析揭示了临床异质性,并评估了肺腺癌的免疫治疗潜力
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-20 DOI: 10.1016/j.gendis.2025.101561
Yuqing Ren , Zaoqu Liu , Yi Yue , Siyuan Weng , Hongxia Jia , Jing Li , Ping Li , Chunya Lu , Xinwei Han , Guojun Zhang
{"title":"Multi-omics analysis of epigenetic dysregulation reveals clinical heterogeneity and evaluates the immunotherapeutic potential of lung adenocarcinoma","authors":"Yuqing Ren ,&nbsp;Zaoqu Liu ,&nbsp;Yi Yue ,&nbsp;Siyuan Weng ,&nbsp;Hongxia Jia ,&nbsp;Jing Li ,&nbsp;Ping Li ,&nbsp;Chunya Lu ,&nbsp;Xinwei Han ,&nbsp;Guojun Zhang","doi":"10.1016/j.gendis.2025.101561","DOIUrl":"10.1016/j.gendis.2025.101561","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101561"},"PeriodicalIF":6.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor microenvironment in osteosarcoma: From cellular mechanism to clinical therapy 骨肉瘤的肿瘤微环境:从细胞机制到临床治疗
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-20 DOI: 10.1016/j.gendis.2025.101569
Yihan Yu , Kanglu Li , Yizhong Peng , Zhicai Zhang , Feifei Pu , Zengwu Shao , Wei Wu
{"title":"Tumor microenvironment in osteosarcoma: From cellular mechanism to clinical therapy","authors":"Yihan Yu ,&nbsp;Kanglu Li ,&nbsp;Yizhong Peng ,&nbsp;Zhicai Zhang ,&nbsp;Feifei Pu ,&nbsp;Zengwu Shao ,&nbsp;Wei Wu","doi":"10.1016/j.gendis.2025.101569","DOIUrl":"10.1016/j.gendis.2025.101569","url":null,"abstract":"<div><div>Osteosarcoma, a prevalent primary malignant bone tumor, predominantly affects both elderly and adolescent populations and usually has an unfavorable prognosis. The specific mechanisms underlying its invasive progression remain unclear. The tumor microenvironment includes not only cancer cells but also bone-related cells, immune cells, tumor-associated nerve cells, and cell-secreted factors. The cooperative and competitive interactions among these cellular components contribute to the proliferation, progression, metastasis, and immune evasion of osteosarcoma. Alterations in bone-related cells, resulting from oncogenic changes, can rapidly increase bone density or aggravate bone loss, thereby promoting the survival of osteosarcoma cells. During the progression of osteosarcoma, genetic alterations in tumor cells lead to changes in extracellular matrix components, influencing the variation in cell-secreted factors, promoting immunosuppression within the tumor microenvironment, and consequently affecting tumor proliferation and progression. This review summarizes the roles of tumor microenvironment components in the pathogenesis of osteosarcoma and discusses existing therapeutic targets. The findings suggest potential research directions for further investigation of osteosarcoma, provide novel insights into the development of osteosarcoma, and may guide the development of more effective anti-tumor strategies.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 5","pages":"Article 101569"},"PeriodicalIF":6.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SIRT5 promotes the osteo-inductive potential of BMP9 by stabilizing the HIF-1α protein in mouse embryonic fibroblasts SIRT5通过稳定小鼠胚胎成纤维细胞中HIF-1α蛋白来促进BMP9的成骨诱导潜能
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-18 DOI: 10.1016/j.gendis.2025.101563
Lu Liu , Fanglin Ye , Yue Jiang , Wenting Liu , Dongmei He , Wenge He , Xiang Gao , Hang Liu , Junyi Liao , Baicheng He , Fang He
{"title":"SIRT5 promotes the osteo-inductive potential of BMP9 by stabilizing the HIF-1α protein in mouse embryonic fibroblasts","authors":"Lu Liu ,&nbsp;Fanglin Ye ,&nbsp;Yue Jiang ,&nbsp;Wenting Liu ,&nbsp;Dongmei He ,&nbsp;Wenge He ,&nbsp;Xiang Gao ,&nbsp;Hang Liu ,&nbsp;Junyi Liao ,&nbsp;Baicheng He ,&nbsp;Fang He","doi":"10.1016/j.gendis.2025.101563","DOIUrl":"10.1016/j.gendis.2025.101563","url":null,"abstract":"<div><div>Bone morphogenetic protein 9 (BMP9) exhibits remarkable osteogenic potential. However, the intricate mechanisms driving this function of BMP9 remain elusive. This study endeavors to investigate the potential role of sirtuin 5 (SIRT5) in enhancing BMP9's osteogenic capacity and decipher the underlying molecular pathways. To achieve this aim, we employed real-time PCR, western blotting, histochemical staining, and a cranial defect repair model to assess the impact of SIRT5 on BMP9-mediated osteogenesis. We utilized real-time PCR, western blotting, immunofluorescent staining, and immunoprecipitation assay to explore the associated mechanisms. Our results revealed that SIRT5 significantly up-regulated BMP9-induced osteogenic markers, while SIRT5 knockdown reduced their expression. Concurrently, hypoxia-inducible factor 1 subunit alpha (HIF-1α) level was increased by SIRT5, but reduced by SIRT5 knockdown. Notably, HIF-1α potentiated the SIRT5's ability to strengthen BMP9's osteogenic potential, whereas HIF-1α silencing reduced this effect, which was confirmed by bone defect repair assay. The acetylation and malonylation levels of HIF-1α were reduced by SIRT5, which may enhance its stability to promote BMP9's osteogenic effect. Conversely, SIRT5 knockdown reversed these effects and promoted the degradation of HIF-1α. Collectively, our results demonstrated that the BMP9's osteogenic potential could be promoted by SIRT5, potentially through stabilizing HIF-1α by reducing its acetylation and malonylation modification. This discovery may offer a novel strategy to accelerate bone tissue engineering by enhancing osteogenic differentiation, and it also sheds light on the possible mechanisms underlying BMP9-mediated osteogenic differentiation.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 4","pages":"Article 101563"},"PeriodicalIF":6.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease 乳酸转运体MCT4调节脂质代谢和炎症中枢基因,以减轻非酒精性脂肪性肝病的细胞内脂质积累
IF 6.9 2区 医学
Genes & Diseases Pub Date : 2025-02-15 DOI: 10.1016/j.gendis.2025.101554
Yannian Gou , Aohua Li , Xiangyu Dong , Ailing Hao , Jiajia Li , Han Xiang , Saidur Rahaman , Tong-Chuan He , Jiaming Fan
{"title":"Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease","authors":"Yannian Gou ,&nbsp;Aohua Li ,&nbsp;Xiangyu Dong ,&nbsp;Ailing Hao ,&nbsp;Jiajia Li ,&nbsp;Han Xiang ,&nbsp;Saidur Rahaman ,&nbsp;Tong-Chuan He ,&nbsp;Jiaming Fan","doi":"10.1016/j.gendis.2025.101554","DOIUrl":"10.1016/j.gendis.2025.101554","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) patients have multiple metabolic disturbances, with markedly elevated levels of lactate. Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications. Monocarboxylate transporter 4 (MCT4) is highly expressed in hepatocytes and responsible for transporting intracellular lactate out of the cell. To explore whether elevated MCT4 levels played any role in NAFLD development, we overexpressed and silenced MCT4 in hepatocytes and performed a comprehensive <em>in vitro</em> and <em>in vivo</em> analysis. Our results revealed that MCT4 overexpression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism. Conversely, silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites, resulting in hepatic steatosis. In a mouse model of NAFLD, we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis. Mechanistically, MCT4 alleviated hepatic steatosis by regulating a group of hub genes such as <em>Arg2</em>, <em>Olr1</em>, <em>Cd74</em>, <em>Mmp8, Irf7</em>, <em>Spp1</em>, and <em>Apoe</em>, which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response, such as PPAR, HIF-1, TNF, IL-17, PI3K-AKT, Wnt, and JAK-STAT. Collectively, our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 4","pages":"Article 101554"},"PeriodicalIF":6.9,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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