Bilirubin Catabolism induces Plasminogen-Activator Inhibitor 1 (PAI-1) worsening Metabolic Dysfunction

胆红素分解代谢诱导纤溶酶原激活剂抑制剂 1 (PAI-1) 恶化代谢功能障碍

• 批准号: 10750132
• 负责人: Zachary A Kipp
• 金额: $ 3.37万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750132
• 关键词: Adipose tissue; Affect; Antioxidants; Arterial Fatty Streak; Bilirubin; Binding; Blood Pressure; Blood Vessels; Body Weight; Calories; Cardiovascular Diseases; Cardiovascular system; Catabolism; Cause of Death; Cessation of life; Cholesterol; Circulation; Coagulation Process; Data; Development; Diet; Environment; Enzymes; Excretory function; Fat-Restricted Diet; Fatty acid glycerol esters; Fellowship; Fibrosis; Financial Hardship; Foundations; Future; Generations; Genetic Polymorphism; Gilbert Disease; Glucuronic Acids; Goals; Healthcare Systems; Heart; Heart Diseases; Heart failure; Heme; Hepatic; High Fat Diet; Hormonal; Human; Intestines; Knock-out; Knockout Mice; Lead; Link; Liver; Measures; Mediator; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mus; Nuclear Receptors; Obese Mice; Obesity; PPAR alpha; Pathway interactions; Patients; Physiological; Plasma; Plasminogen Activator Inhibitor 1; Portal System; Prevention; Production; Proteins; RNA Interference; Research; Research Proposals; Research Technics; Risk; Risk Factors; Role; Scientist; Serum; Structure; Technology; Testing; Therapeutic; Thinness; Training; Translating; Travel; UGT1A1 gene; United States; Water; Woman; Work; absorption; bile duct; cardioprotection; cardiovascular disorder prevention; cardiovascular disorder risk; career; comorbidity; diet-induced obesity; feeding; glucose tolerance; gut microbiota; improved; men; mouse development; new therapeutic target; novel marker; novel therapeutics; obese patients; prevent; promoter; therapeutic target; tool; transcriptome; transcriptome sequencing

Summary: Urobilin is formed in the intestine as a biproduct of conjugated bilirubin catabolism. Currently, the physiological function of urobilin is unknown. Human association studies have indicated a positive correlation to obesity and cardiovascular diseases (CVD). Since obesity is a major risk factor for the development of CVD, we hypothesized that urobilin levels might change with the altered metabolic state and induce adiposity. To determine the role of urobilin in lean mice, we treated C57/bl6 mice on a normal-chow diet with urobilin for 4 weeks. We found that urobilin had no effect on body weight but significantly increased adiposity in the inguinal white adipose tissue (iWAT) depot compared to the vehicle-treated mice. To determine how urobilin changes the transcriptome profile in the iWAT, we preformed RNA-sequencing which showed that urobilin increases the expression of Serpine1 mRNA. Serpine1 is translated into the protein plasminogen activator inhibitor-1 (PAI-1). PAI-1 is secreted into circulation, promoting a prothrombotic environment, and is thought to increase the risk of CVD. The goal of this research proposal is to determine whether urobilin induces CVD via PAI-1 and if this mechanism is a link between CVD and obesity. We will investigate if lowering plasma urobilin is a possible therapeutic for the treatment and prevention of CVD. To study this, in Aim 1, we will use PAI-1 knockout (KO) mice and littermate controls treated with urobilin or vehicle while on a high-fat or calorie-match low-fat diets. We expect the PAI-1KO mice will be protected from urobilin induced CVD. In Aim 2, we will use diet-induced obese (DIO) mice treated with a liver- specific GalNac-Ugt1a1-RNAi or GalNac-scramble control to suppress hepatic Ugt1a1, which is responsible for initiating the conjugation of bilirubin that leads to elevated urobilin production. We show preliminary data that the RNAi technology suppresses Ugt1a1 94.7% and that this leads to a significant (p<0.01) decrease in plasma urobilin and an increase in plasma unconjugated bilirubin. We expect that the suppression of Ugt1a1 will protect the mice from the development of CVD by lowering urobilin levels, increasing unconjugated bilirubin, preventing adiposity and high PAI-1 plasma levels. This is the first proposed mechanism of urobilin in promoting the development of CVD, which we will extensively study to better understand how to reverse its deleterious effects. This fellowship will provided critical training in research techniques, scientific training and professional development to give me the tools to become a successful independent scientist.

总结： 尿胆素在肠中形成为结合胆红素催化剂的双产物。目前，生理 尿胆素的功能尚不清楚。人类协会的研究表明，肥胖和 心血管疾病（CVD）。由于肥胖是心血管疾病发展的主要危险因素，我们假设 尿胆素水平可能会随着代谢状态的改变而改变，并诱导肥胖。确定的作用 为了研究瘦小鼠中的尿胆素，我们用尿胆素处理正常饮食的C57/bl 6小鼠4周。我们发现 尿胆素对体重没有影响，但显著增加腹股沟白色脂肪组织的肥胖 与媒介物处理的小鼠相比，iWAT储库。为了确定尿胆素如何改变转录组谱， 在iWAT中，我们进行了RNA测序，结果显示尿胆素增加Serpine 1的表达， mRNA。Serpine 1被翻译成蛋白质纤溶酶原激活物抑制剂-1（派-1）。派-1被分泌到 血液循环，促进血栓形成前环境，并被认为会增加CVD的风险。这个目标 一项研究计划是确定尿胆素是否通过派-1诱导CVD，以及这种机制是否与 心血管疾病和肥胖。我们将研究降低血浆尿胆素是否是一种可能的治疗方法， 预防CVD。为了研究这一点，在目标1中，我们将使用派-1敲除（KO）小鼠和同窝对照， 与尿胆素或赋形剂同时进行高脂肪或热量匹配的低脂饮食。我们预计派-1 KO小鼠将 防止尿胆素诱导的CVD。在目标2中，我们将使用经肝脏- 特异性GalNac-Ugt 1a 1-RNAi或GalNac-scramble控制以抑制肝Ugt 1a 1，其负责 引发胆红素的结合，导致尿胆素产生升高。初步数据显示， RNAi技术抑制Ugt 1a 1 94.7%，这导致血浆中Ugt 1a 1的显著（p<0.01）降低。 尿胆素和血浆未结合胆红素升高。我们希望Ugt 1a 1的抑制将保护 通过降低尿胆素水平，增加未结合胆红素，预防 肥胖和高派-1血浆水平。这是第一个提出的机制，尿胆素促进 我们将广泛研究CVD的发展，以更好地了解如何扭转其有害影响。 该奖学金将提供研究技术，科学培训和专业培训方面的关键培训。 发展给我的工具，成为一个成功的独立科学家。