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. .

项目概要/摘要 自从引入有效的联合抗逆转录病毒疗法（cART）以来，艾滋病毒感染已得到转变 从一种致命的疾病变成一种慢性病。肝病已成为非健康问题的第二大原因 艾滋病毒感染者 (PLWH) 与艾滋病相关的死亡。非酒精性脂肪肝（NAFLD）是主要的疾病 在美国，这是一种慢性肝病，困扰着大约 30% 的成年人。 PLWH 患病率较高 NAFLD 的发生率高达 53%，这不仅与非酒精性炎症的发生频率较高有关 脂肪性肝炎（NASH）还会加速肝纤维化进展。此外，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。虽然最近的研究 复制了 PLWH/NAFLD 中看到的加速纤维化进展，但精确的机制仍然存在 定义不明确。我们和其他人在该领域处于领先地位，证明艾滋病毒本身会诱导促纤维化程序 通过多种途径进入肝脏。 Hippo 信号通路通过以下方式控制细胞增殖和纤维形成 YAP 转录共激活因子，通过结合 TEAD、SMAD1/2/3 和 其他网站。我们最近的工作表明，NAFLD 患者中 YAP 相关基因表达增加 纤维化和小鼠 NASH 模型。我们还观察到纤维化相关参数显着降低 肝细胞特异性 YAP 基因敲除小鼠接受 NASH 饮食喂养。我们还表明 HIV 会诱导 YAP 激活 通过 LPA/PI3K 和 AKT 途径在肝细胞和巨噬细胞中发挥作用。因此，HIV 和 NAFLD 可能 在 YAP 激活水平上合作，促进纤维形成和肝损伤。肝脏和单核细胞- 衍生的巨噬细胞因 HIV 感染而失调并在肝损伤期间极化，可能有助于 NAFLD 和 HIV 相关肝病。研究发现肝脏中的巨噬细胞含量增加 PLWH 等人已将 YAP 激活与巨噬细胞浸润联系起来。然而，综合研究 YAP 激活对关键细胞类型（肝细胞、巨噬细胞和 HSC）的体外和体内影响 缺乏驱动 PLWH 纤维形成的因子。我们假设 HIV 和 NAFLD 发挥独立且相加的作用 对巨噬细胞和肝细胞群中 YAP 激活的影响，进而加速肝纤维化 通过对 HSC 的作用来取得进展。在该提案中，使用新型共培养测定法、离体肝组织、 和人源化小鼠模型，结合肝脏发病机制和 HIV 病毒学/发病机制的努力 专家们，我们将：（1）定义YAP信号对巨噬细胞极化、肝细胞和肝脏的贡献 HIV/NAFLD 中星状细胞 (HSC) 的激活。 (2)评估cART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 的效果 抑制 HIV/NAFLD 中的纤维形成。详细了解上下游监管机构 YAP 在 NAFLD/HIV 中的研究可能会发现新的 NAFLD 抗纤维化策略，从而阻止这种高度 PLWH 中普遍存在进行性肝病。 。