YAP signaling in the pathogenesis of NAFLD in people living with HIV

HIV 感染者 NAFLD 发病机制中的 YAP 信号传导

• 批准号: 10809266
• 负责人: RAYMOND T CHUNG
• 金额: $ 82.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-26 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809266
• 关键词: 3-Dimensional; Acceleration; Adult; Binding; Biological Assay; Cell Culture Techniques; Cell Proliferation; Cessation of life; Chronic; Coculture Techniques; Data; Diet; Disease; Exposure to; Fibrosis; Frequencies; Gene Expression; Genes; Genetic Transcription; HIV; HIV Infections; Hepatic; Hepatic Stellate Cell; Hepatocyte; High Prevalence; Human; In Vitro; Incidence; Infiltration; Inflammatory; Knockout Mice; Link; Liver; Liver Fibrosis; Liver diseases; MAP Kinase Gene; Macrophage; Modeling; Mus; Nonesterified Fatty Acids; Organ; PI3K/AKT; PIK3CG gene; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Phenotype; Population; Proto-Oncogene Proteins c-akt; Regimen; Reporting; Role; Signal Pathway; Signal Transduction; Site; Tissues; Transcription Coactivator; Transforming Growth Factor beta; Verteporfin; Wild Type Mouse; Work; antiretroviral therapy; cell type; chronic liver disease; defined contribution; fibrogenesis; gene induction; genetic signature; humanized mouse; in vivo; inhibitor; kidney fibrosis; liver inflammation; liver injury; monocyte; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; p38 Mitogen Activated Protein Kinase; prevent; programs; virology

Project Summary/Abstract Since the introduction of effective combination antiretroviral therapy (cART), HIV infection has been converted from a fatal disease into a chronic condition. Liver disease has emerged as the second leading cause of non- AIDS related death in persons living with HIV (PLWH). Nonalcoholic fatty liver disease (NAFLD) is the leading form of chronic liver disease in the U.S., afflicting approximately 30% of adults. PLWH have a high prevalence of NAFLD with rates as high as 53%, associated with not only higher frequency of the inflammatory non-alcoholic steatohepatitis (NASH) but also accelerated liver fibrosis progression. Moreover, in NAFLD/HIV, there is a disproportionate burden of progressive NASH and fibrosis compared with HIV(-) NAFLD. While recent studies have replicated the accelerated fibrosis progression seen in PLWH/NAFLD, the precise mechanisms remain poorly defined. We and others have led the field in demonstrating that HIV itself induces a profibrogenic program in the liver via several pathways. The Hippo signaling pathway controls cell proliferation and fibrogenesis through YAP transcriptional co-activators that regulate more than 400 genes through binding to TEAD, SMAD1/2/3 and other sites. Our recent work has shown increases in YAP-related gene expression among NAFLD patients with fibrosis and in mouse NASH models. We also observed a significant reduction in fibrosis-related parameters in hepatocyte-specific YAP knockout mice fed a NASH diet. We have also shown that HIV induces YAP activation in hepatocytes and macrophages via the LPA/PI3K and AKT pathways. Therefore, HIV and NAFLD likely cooperate at the level of YAP activation to contribute to fibrogenesis and liver damage. Hepatic and monocyte- derived macrophages, dysregulated by HIV infection and polarized during liver injury, are likely to contribute to NAFLD and HIV-related liver disease. Studies have observed increased macrophage content in the livers of PLWH and others have linked YAP activation to macrophage infiltration. However, comprehensive studies of the in vitro and in vivo effects of YAP activation among the key cell types (hepatocytes, macrophages, and HSCs) that drive fibrogenesis in PLWH are lacking. We hypothesize that HIV and NAFLD exert independent and additive effects on YAP activation in both macrophage and hepatocyte populations that in turn accelerate hepatic fibrosis progression through their action on HSCs. In this proposal, using novel coculture assays, ex vivo liver tissue, and a humanized mouse model and combining the efforts of liver pathogenesis and HIV virology/pathogenesis experts, we will: (1) define the contribution of YAP signaling to macrophage polarization, hepatocyte and hepatic stellate cell (HSC) activation in HIV/NAFLD.; (2) assess the effect of cART regimens on macrophage, hepatocyte and HSC phenotypes and YAP activation in models of HIV/NAFLD.; and (3) determine the effects of YAP inhibition on fibrogenesis in HIV/NAFLD. A detailed understanding of the upstream and downstream regulators of YAP in NAFLD/HIV is likely to uncover novel antifibrotic strategies for NAFLD that could block this highly prevalent progressive liver disease in PLWH. .

项目摘要/摘要 自从引入有效组合抗逆转录病毒疗法（CART）以来，HIV感染已转化 从致命疾病到慢性病。肝病已成为非 - 与艾滋病毒（PLWH）患者相关的艾滋病死亡。非酒精性脂肪肝病（NAFLD）是领先的 在美国，慢性肝病的形式折磨了约30％的成年人。 PLWH患病率很高 NAFLD的速率高达53％，不仅与炎症性非酒精性频率更高有关 脂肪性肝炎（NASH），但也加速了肝纤维化进展。而且，在NAFLD/HIV中，有一个 与HIV（ - ）NAFLD相比，进行性NASH和纤维化的负担不成比例。而最近的研究 已经复制了在PLWH/NAFLD中看到的加速纤维化进展，确切的机制仍然存在 定义不佳。我们和其他人领导了该领域，证明艾滋病毒本身会诱导纤维化程序 在肝脏中通过多种途径。河马信号通路通过通过 YAP转录共激活因子通过结合tead，Smad1/2/3和 其他站点。我们最近的工作表明，NAFLD患者的YAP相关基因表达增加 纤维化和小鼠NASH模型。我们还观察到与纤维化相关参数的显着降低 肝细胞特异性的YAP敲除小鼠喂了纳什饮食。我们还表明，HIV诱导YAP激活 通过LPA/PI3K和AKT途径在肝细胞和巨噬细胞中。因此，HIV和NAFLD可能 在YAP激活水平上合作，有助于纤维化和肝损伤。肝和单核细胞 衍生的巨噬细胞因HIV感染而失调，在肝损伤期间极化，可能有助于 NAFLD和与HIV相关的肝病。研究观察到巨噬细胞含量增加 PLWH和其他人将YAP激活与巨噬细胞浸润有关。但是，关于 关键细胞类型（肝细胞，巨噬细胞和HSC）中YAP激活的体外和体内效应 缺少PLWH中的纤维化。我们假设HIV和NAFLD独立和添加剂 对巨噬细胞和肝细胞种群中YAP激活的影响，又加速了肝纤维化 通过他们对HSC的行动进展。在此提案中，使用新型的共培养测定，离体肝组织， 以及人性化的小鼠模型，并结合了肝脏发病机理和HIV病毒学/发病机理的努力 专家，我们将：（1）定义YAP信号对巨噬细胞极化，肝细胞和肝的贡献 HIV/NAFLD中的星状细胞（HSC）激活。 （2）评估卡车方案对巨噬细胞，肝细胞的影响 HIV/NAFLD模型中的HSC表型和YAP激活。 （3）确定YAP的影响 抑制HIV/NAFLD中纤维化的抑制作用。对上游和下游监管机构的详细理解 NAFLD/HIV中的YAP可能会发现NAFLD的新型抗纤维化策略可能会阻止这种高度 PLWH中流行的进行性肝病。 。