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

揭示 GPR75 作为脂肪酸转运蛋白激活剂在非酒精性脂肪性肝病 (NAFLD) 中的作用

• 批准号: 10666762
• 负责人: Victor Garcia
• 金额: $ 16.4万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10666762
• 关键词: Address; Adult; Affinity; Alanine Transaminase; Alleles; Angiotensin II; Apoptosis; Aspartate Transaminase; Automobile Driving; Binding; Binding Sites; Body Composition; Cardiometabolic Disease; Cause of Death; Cells; Chronic; Chronic Kidney Failure; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Coupled; Data; Dependence; Deposition; Development; Diabetes Mellitus; Disease; Dose; Eicosatetraenoic Acids; Exposure to; Fatty Acids; Fibrosis; Foundations; G-Protein-Coupled Receptors; GPR75 gene; Genes; Genetic; Genome; Glucose; Health; Health Care Costs; Healthcare Systems; Heart Diseases; Heart failure; HepG2; Hepatocyte; High Fat Diet; Histopathology; Human; Hypertension; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Insulin Resistance; Interleukin-6; Kidney; Learning; Ligands; Lipids; Liver; Mediating; Molecular; Mus; Obesity; Orphan; Outcome; Pathogenesis; Pathologic; Peptides; Phenotype; Plague; Prevalence; Prevention; Profibrotic signal; Proteins; Protocols documentation; Public Health; RANTES; Renin-Angiotensin System; Research; Role; Science; Severities; Signal Pathway; Signal Transduction; Stroke; TNF gene; Testing; Thinness; Time; United States; United States National Institutes of Health; Variant; Water; Weight Gain; adipokines; cell injury; diet-induced obesity; disease phenotype; druggable target; exome sequencing; fatty acid transport; feeding; global health; in vivo; innovation; insulin tolerance; knock-down; lipid mediator; liver injury; loss of function; multi-ethnic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obesity development; obesity treatment; pharmacologic; prevent; programs; protective effect; protein expression; receptor; translational applications; uptake

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.

肥胖症的患病率是全球关注的关注点，在美国有近5个成年人（42.4％）患有肥胖症。快速 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 - 酒精脂肪肝病（NAFLD）。最近，有几种可理解的孤儿G的功能变异的丧失 蛋白质偶联受体（GPCR），GPR75被鉴定出与瘦肉和受保护的表型有关 在全球多民族外显子组中反对肥胖，有64万多人。我们的小组有用 在这些研究中，我们的建议旨在研究GPR75在肥胖和NAFLD中的作用。具体来说，我们 假设GPR75与其高亲和力配体的配对，20-Heete，一种血管活性和促炎性脂质， 加剧饮食引起的肥胖症，驱动NaFL和非酒精性脂肪性肝炎（NASH），其特征是 明显的炎症，细胞损伤和纤维化。为了检验这一假设，我们提出了两个具体目标。目标1寻求 确定20-HETE/GPR75配对有助于肥胖驱动的发病机理的程度 nafld/nash。此目的将评估小鼠肥胖，糖尿病/胰岛素抵抗和肝损害的严重程度 GPR75缺乏，暴露于20-HETE的海拔和跨时间的高脂饮食喂养方案。小说 水溶性GPR75受体阻滞剂AAA将用于评估疾病发展的依赖性和 在20-Hete-GPR75配对上进行进程。 AIM 2旨在识别20-HETE-GPR75的细胞机制 配对驱动力增加了脂肪酸的摄取和炎症，这会导致NAFLD。具体来说，它将确定 GPR75通过20-HETE的激活如何刺激肝细胞中脂肪酸转运蛋白2（FATP2）的活性。 我们还将评估20-Hete和脂肪酸影响的组合如何驱动各种促炎和 纤维化信号。此特定目的还将结合使用AAA（GPR75受体阻滞剂）和肝细胞 缺乏GPR75。拟议的研究背后的含义具有很高的创新性，因为它们将奠定基础 随着我们继续进一步了解GPR75在肥胖和NAFLD/NASH中的作用。我们的初步 数据强烈表明GPR75是具有转化应用的可吸毒目标，用于预防和处理 肥胖和NAFLD/NASH，目前困扰全球医疗体系的疾病。因此，我们相信这 应用非常符合IDG的主动性，该计划支持与人类中的GPCR相关的研究 健康与疾病。