Uncovering the role of GPR75 as an activator of fatty acid transporters in non-alcoholic fatty liver disease (NAFLD)

肥胖症的患病率是全球关注的问题，在美国，近五分之二的成年人（42.4%）患有肥胖症。快速和 体重增加的持续增加导致各种肥胖驱动的并发症和健康结果，包括非 酒精性脂肪肝（NAFLD）。最近，几个预测的功能损失的变种，未充分研究的孤儿G 蛋白偶联受体（GPCR），GPR 75被鉴定为与瘦肉和保护性表型相关 在全球范围内对超过640，000人进行的多种族外显子组测序中，我们的团队 在这些研究中，我们的建议旨在研究GPR 75在肥胖和NAFLD中的作用。我们特别 假设GPR 75与其高亲和力配体20-HETE（一种血管活性和促炎脂质）的配对， 加剧饮食诱导的肥胖，驱动NAFL和非酒精性脂肪性肝炎（NASH），其特征在于 明显的炎症细胞损伤和纤维化为了验证这一假设，我们提出了两个具体目标。目标1： 确定20-HETE/GPR 75配对在多大程度上有助于肥胖驱动的 NAFLD/NASH。这一目标将评估小鼠肥胖、糖尿病/胰岛素抵抗和肝损伤的严重程度 缺乏GPR 75并随时间暴露于20-HETE升高和高脂饮食喂养方案。一种新型 水溶性GPR 75受体阻断剂AAA将用于评估疾病发展的依赖性， 20-HETE-GPR 75配对的进展。目的2旨在鉴定20-HETE-GPR 75通过其在细胞内表达的细胞机制。 配对驱动增加脂肪酸摄取和炎症，这有助于NAFLD。具体来说，它将决定 通过20-HETE激活GPR 75如何刺激肝细胞中脂肪酸转运蛋白2（FATP 2）的活性。 我们还将评估20-HETE和脂肪酸内流的组合如何驱动各种促炎性和炎症反应， 促纤维化信号。该特定目标还将包括AAA（GPR 75受体阻断剂）和肝细胞的使用。 缺乏GPR 75。拟议研究背后的含义是高度创新的，因为它们将奠定基础 我们将继续了解GPR 75在肥胖和NAFLD/NASH中的作用。我们的初步 数据有力地表明，GPR 75是一种可药物化的靶点，具有预防和治疗以下疾病的转化应用： 肥胖和NAFLD/NASH，目前困扰全球医疗保健系统的疾病。因此，我们认为， 应用程序与IDG的倡议非常吻合，以支持与人类中特征不佳的GPCRS相关的研究。 健康和疾病。

The prevalence of obesity is a global concern with nearly 2 in 5 adults (42.4%) in the US having obesity. Rapid and sustained increases in weight gain result in various obesity-driven complications and health outcomes including non- alcoholic fatty liver disease (NAFLD). Recently, several predicted loss of function variants of the understudied orphan G protein- coupled receptor (GPCR), GPR75 were identified to be associated with leanness and a protective phenotype against obesity in a world-wide multi-ethnic exome sequencing of over 640,000 individuals. Our group was instrumental in these studies and our proposal seeks to examine the role of GPR75 in obesity and NAFLD. Specifically, we hypothesize that the pairing of GPR75 to its high-affinity ligand, 20-HETE, a vasoactive and proinflammatory lipid, exacerbating diet-induced obesity, driving NAFL and nonalcoholic steatohepatitis (NASH) which is characterized by pronounced inflammation, cell damage and fibrosis. To test this hypothesis, we propose two specific aims. Aim 1 seeks to determine the degree to which the pairing of 20-HETE/GPR75 contributes to the pathogenesis of obesity-driven NAFLD/NASH. This aim will evaluate the severity of obesity, diabetes/insulin resistance and liver damage in mice deficient in GPR75 and exposed to elevations in 20-HETE and a high-fat diet feeding protocol across time. A novel water-soluble GPR75 receptor blocker, AAA, will be used to assess the dependency of the disease development and progression on 20-HETE-GPR75 pairing. Aim 2 looks to identify the cellular mechanism by which the 20-HETE-GPR75 pairing drives increases in fatty acid uptake and inflammation which contribute to NAFLD. Specifically, it will determine how the activation of GPR75 via 20-HETE stimulates the activity of the fatty acid transporter 2 (FATP2) in hepatocytes. We will also evaluate how the combination of 20-HETE and fatty acid influx drive various proinflammatory and profibrotic signals. This particular aim will also incorporate the use of AAA (GPR75 receptor blocker) and hepatocytes deficient in GPR75. The implications behind the proposed research are highly innovative as they will lay the foundation and fundamentals as we continue to learn more about the role of GPR75 in obesity and NAFLD/NASH. Our preliminary data strongly suggest that GPR75 is a druggable target with translational applications for the prevention and treatment of obesity and NAFLD/NASH, diseases that presently plague the global healthcare system. Therefore, we believe that this application fits strongly with the IDG’s initiative to support studies pertaining to poorly characterized GPCRS in human health and disease.