Regulation of Cholesterol Catabolism by Bile Acids

胆汁酸调节胆固醇分解代谢

• 批准号: 9899227
• 负责人: Jongsook Kim Kemper
• 金额: $ 39.65万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899227
• 关键词: Attention; Bile Acids; Binding; Binding Sites; Biochemical; Cardiovascular Diseases; Catabolism; ChIP-seq; Cholesterol; Cirrhosis; Clinical; Clinical Trials; CpG Islands; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; Data; Diabetes Mellitus; Diet; Down-Regulation; Epidemic; Epigenetic Process; FGF19 gene; Fibrosis; Genes; Genetic Transcription; Genomics; Goals; Hepatic; High Fat Diet; Hormones; Human; Impairment; Individual; Intervention; Intestinal Hormones; Knockout Mice; Lipids; Liver; Liver diseases; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Molecular; Monitor; Mus; NR0B2 gene; Nuclear Orphan Receptor; Nuclear Receptors; Obese Mice; Obesity; Obesity associated liver disease; Patients; Pharmacology; Phosphorylation; Physiological; Physiology; Proteins; Publishing; Regulation; Repression; Role; SRE-1 binding protein; Sampling; Signal Transduction; Signaling Molecule; Site; Steatohepatitis; Testing; Therapeutic; Triglycerides; Viral; analog; base; diabetes risk; diagnostic biomarker; epigenetic regulation; gene repression; in vivo; insulin sensitizing drugs; lipid biosynthesis; lipid metabolism; liver metabolism; metabolic abnormality assessment; mouse model; mutant; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; recruit; response

Summary Obesity has become a global epidemic and greatly increases the risk for diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Nearly 80% of obese people develop NAFLD, which progresses to steatohepatitis (NASH) and further to end-stage liver diseases, such as fibrosis, cirrhosis, and liver cancer, but good therapeutic options to treat NAFLD are not available. The hallmark of NAFLD is abnormal accumulation of triglyceride (TG) in the liver due to dysregulated lipid metabolism. Bile acids (BAs) are recently recognized signaling molecules that profoundly impact metabolism and counteract obesity. The BA-induced intestinal hormone, FGF15/19 (mFGF15. hFGF19), has received great attention because its lipid-lowering and insulin-sensitizing effects and, thus, its therapeutic potential in treating obesity and diabetes. However, little is known about how FGF15/19 controls lipid metabolism. The overall goal of this application is to determine how an orphan nuclear receptor Small Heterodimer Partner (SHP, NR0B2) mediates postprandial actions of FGF15/19 by epigenetic regulation of hepatic lipid metabolism. We have preliminary data showing that FGF19 treatment induced recruitment of DNA methyltransferase-3a (DNMT3a) to key lipogenic genes in a SHP-dependent manner, and liver-specific downregulation of SHP or DNMT3a led to decreased 5-methyl cytosine (5mC) DNA levels at these genes and increased liver TG levels, suggesting a novel function of SHP and DNMT3a in hepatic lipogenesis. Based these exciting preliminary data, we hypothesize that SHP physiologically mediates epigenetic repression of hepatic lipogenesis by recruiting DNMT3a, in response to FGF15 signaling in the late fed-state, but this FGF15- SHP-DNMT3a regulatory axis is disrupted in obesity. To test this hypothesis, we will 1) determine the role and the underlying mechanisms of how the FGF15-SHP-DNMT3a regulatory axis mediates epigenetic repression of hepatic lipogenic genes, and then, 2) investigate the in vivo function of hepatic SHP and DNMT3a in regulation of liver lipid metabolism, focusing on de novo lipogenesis, and dysregulation of this regulatory axis in obesity in mice and determine human relevance by analysis of liver samples from NAFLD patients. To achieve these goals, multifaceted approaches, including molecular/biochemical, metabolic, and epigenetic studies and global genomic analyses, will be utilized in SHP-LKO and FGF15-KO mice, and mouse models generated by viral-mediated expression and downregulation of proteins. Impact: Our expertise on transcriptional and epigenetic control of liver lipid metabolism by nuclear receptors uniquely qualifies us to carry out this project. This proposal will test whether SHP and DNMT3a mediate FGF15/19 actions in hepatic lipid metabolism, and may reveal effective approaches for developing new therapeutic targets for NAFLD and diagnostic biomarkers to monitor its progression.

概括 肥胖已成为全球流行病，大大增加了患糖尿病、心血管疾病、 和非酒精性脂肪肝（NAFLD）。近 80% 的肥胖者患有 NAFLD， 进展为脂肪性肝炎 (NASH)，并进一步发展为终末期肝病，如纤维化、肝硬化和 肝癌，但尚无治疗 NAFLD 的良好治疗方案。 NAFLD 的特点是 由于脂质代谢失调，甘油三酯（TG）在肝脏中异常积累。胆汁酸 （BA）是最近公认的信号分子，可深刻影响新陈代谢并抵消 肥胖。 BA诱导的肠道激素FGF15/19（mFGF15.hFGF19）受到极大关注 因为它具有降脂和胰岛素增敏作用，因此具有治疗潜力 肥胖和糖尿病。然而，人们对 FGF15/19 如何控制脂质代谢知之甚少。整体 该应用的目标是确定孤儿核受体小异二聚体伴侣（SHP， NR0B2) 通过肝脂质代谢的表观遗传调节介导 FGF15/19 的餐后作用。 我们的初步数据显示 FGF19 治疗诱导 DNA 甲基转移酶 3a 的募集 (DNMT3a) 以 SHP 依赖性方式影响关键的脂肪生成基因，以及 SHP 或肝脏特异性下调 DNMT3a 导致这些基因的 5-甲基胞嘧啶 (5mC) DNA 水平降低并增加肝脏 TG 水平，表明 SHP 和 DNMT3a 在肝脂肪生成中具有新功能。基于这些令人兴奋的 初步数据显示，我们假设 SHP 在生理上介导肝脏的表观遗传抑制 通过招募 DNMT3a 来促进脂肪生成，以响应进食状态后期的 FGF15 信号传导，但这种 FGF15- SHP-DNMT3a 调节轴在肥胖中被破坏。为了检验这个假设，我们将 1）确定角色 以及FGF15-SHP-DNMT3a调控轴介导表观遗传的潜在机制 抑制肝脂肪生成基因，然后，2) 研究肝 SHP 的体内功能和 DNMT3a 调节肝脏脂质代谢，重点关注从头脂肪生成及其失调 小鼠肥胖的调节轴并通过分析 NAFLD 的肝脏样本确定人类相关性 患者。为了实现这些目标，需要采取多方面的方法，包括分子/生物化学、代谢、 表观遗传学研究和全局基因组分析将用于 SHP-LKO 和 FGF15-KO 小鼠，以及 通过病毒介导的蛋白质表达和下调产生的小鼠模型。 影响：我们在通过核对肝脏脂质代谢进行转录和表观遗传控制方面的专业知识 受体使我们有资格开展这个项目。该提案将测试SHP和DNMT3a是否 介导 FGF15/19 在肝脏脂质代谢中的作用，并可能揭示开发开发的有效方法 NAFLD 的新治疗靶点和监测其进展的诊断生物标志物。