Protective role of adenosine 2A receptor in NAFLD

腺苷2A受体在NAFLD中的保护作用

• 批准号: 8650282
• 负责人: Chaodong Wu
• 金额: $ 31.72万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650282
• 关键词: Adenosine; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Proteins; Bone Marrow Transplantation; Carbohydrates; Cells; Coculture Techniques; Conditioned Culture Media; Development; Diet; Elements; Enzymes; Event; Exhibits; Family; Fatty Liver; Fatty acid glycerol esters; Functional disorder; G-Protein-Coupled Receptors; Gene Expression; Genes; Goals; Hepatic; Hepatocyte; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Knowledge; Kupffer Cells; Leukocytes; Liver; Liver Cirrhosis; Liver diseases; Metabolic; Metformin; Methionine; Mus; Myeloid Cells; Nutrient; Palmitates; Pathogenesis; Phosphorylation; Play; Prevention; Primary carcinoma of the liver cells; Property; Purinergic P1 Receptors; Receptor Activation; Receptor Inhibition; Regulatory Element; Research; Role; Sterols; TNF gene; Testing; Wild Type Mouse; base; cell type; choline deficient diet; cytokine; effective therapy; evidence base; expectation; feeding; in vivo; knock-down; lipid biosynthesis; liver inflammation; macrophage; member; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel strategies; prevent; promoter; public health relevance; receptor; receptor function; research study

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of terminal liver diseases including liver cirrhosis and hepatocellular carcinoma. Growing evidence demonstrates the critical importance of inflammation in the pathogenesis of NAFLD. For instance, nutrient overload triggers inflammation, which can act through stimulating lipogenesis to increase hepatic steatosis. The latter, in turn, can exacerbate liver inflammation and progress to non-alcoholic steatohepatitis (NASH). However, the precise mechanisms underlying the interaction between hepatic steatosis and liver inflammation remain to be elucidated. Thus, the long-term goal of the proposed research is to dissect the metabolic and inflammatory mechanisms underlying NAFLD in order that novel evidence-based approaches can be developed for preventing and/or treating NASH. As a G-protein-coupled receptor, adenosine 2A receptor (A2AR) is abundantly expressed in immune cells and exhibits powerful anti-inflammatory properties. A2AR is also highly expressed in hepatocytes, in which A2AR functions are largely unknown. For this project, the central hypothesis is that the A2AR in hepatocytes and macrophages protects against the development of different aspects of NAFLD in a cell-type-dependent manner. This hypothesis is based on the following novel findings: 1) A2AR deficiency in hepatocytes plays a more important role than A2AR deficiency in myeloid cells (macrophages) in exacerbating high-fat diet (HFD)- induced hepatic steatosis, which is associated with increased hepatic expression of lipogenic enzymes; 2) A2AR deficiency exacerbates HFD-induced liver inflammation, which is likely attributed to increased macrophage/Kupffer cell proinflammatory activation; and 3) A2AR activation by a specific agonist protects mice from HFD-induced NAFLD. Thus, the goal of this project is to define a novel protective role for A2AR in NAFLD. For this purpose, mice that lack A2AR in hepatocytes and/or myeloid cells are generated. For Specific Aim 1, in vivo experiments will be performed to examine the extent to which the A2AR in hepatocytes acts through inhibiting lipogenesis to protect against NAFLD. Moreover, cellular experiments will be performed to elucidate the involvement of SREBP1c and ChREBP in A2AR inhibition of lipogenic gene expression. For Specific Aim 2, in vivo experiments will be performed to examine the extent to which the A2AR in macrophages or hepatocytes protects against NAFLD by suppressing liver inflammatory response. For Specific Aim 3, in vivo experiments will be performed to define A2AR coordination of hepatocyte-macrophage crosstalk in NAFLD. Moreover, in vitro co-culture experiments will be performed to examine the extent to which factors generated by A2AR-deficient macrophages, i.e., TNF? and IL-6, stimulate hepatocyte lipogenesis, and the extent to which factors generated by A2AR-deficient hepatocytes, i.e., palmitate, stimulate macrophage proinflammatory activation. Together, the proposed research will illustrate a new paradigm on NAFLD, and provide the experimental basis for prevention and/or treatment of NASH by means of A2AR activation.

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是终末期肝病最常见的原因之一，包括肝硬变和肝细胞癌。越来越多的证据表明炎症在NAFLD发病机制中的关键作用。例如，营养过载会引发炎症，炎症可以通过刺激脂肪生成来增加肝脏脂肪变性。后者反过来会加剧肝脏炎症，并进展为非酒精性脂肪性肝炎(NASH)。然而，肝脏脂肪变性和肝脏炎症之间相互作用的确切机制仍有待阐明。因此，这项拟议研究的长期目标是剖析NAFLD背后的代谢和炎症机制，以便开发新的循证方法来预防和/或治疗NASH。腺苷2A受体(A2AR)是一种G蛋白偶联受体，在免疫细胞中大量表达，具有强大的抗炎作用。A2AR在肝细胞中也高表达，其功能在很大程度上是未知的。对于这个项目，中心假设是肝细胞和巨噬细胞中的A2AR以一种细胞类型依赖的方式防止NAFLD的不同方面的发展。这一假说基于下列新的发现：1)在加剧高脂饮食(HFD)诱导的肝脏脂肪变性方面，肝细胞中A2AR缺乏比A2AR缺乏发挥更重要的作用；2)A2AR缺乏加剧高脂饮食(HFD)诱导的肝脏炎症，这可能归因于巨噬细胞/Kupffer细胞促炎症激活；以及3)特定激动剂激活A2AR可以保护小鼠免受HFD诱导的NAFLD的影响。因此，该项目的目标是定义A2AR在NAFLD中的新的保护作用。为此，产生了肝细胞和/或髓系细胞中缺乏A2AR的小鼠。对于特定的目的1，将进行体内实验，以检查肝细胞中的A2AR通过抑制脂肪生成来预防NAFLD的程度。此外，还将进行细胞实验，以阐明SREBP1c和ChREBP参与A2AR抑制造脂基因表达的作用。对于特定的目的2，将进行体内实验，以检查巨噬细胞或肝细胞中的A2AR通过抑制肝脏炎症反应来保护NAFLD的程度。针对特定目的3，将进行体内实验，以确定NAFLD中肝细胞-巨噬细胞串扰的A2AR协调。此外，还将进行体外共培养实验，以检测A2AR缺陷的巨噬细胞产生的因子，即肿瘤坏死因子？和IL-6，刺激肝细胞脂肪生成，以及由A2AR缺陷的肝细胞产生的因子，即棕榈酸酯，刺激巨噬细胞前炎症激活的程度。综上所述，本研究将阐明NAFLD的新范式，并为通过激活A2AR来预防和/或治疗NASH提供实验基础。