Novel transcriptional regulators of bile acid metabolism and hepatotoxicity

胆汁酸代谢和肝毒性的新型转录调节因子

• 批准号: 8670488
• 负责人: Peter A Edwards
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670488
• 关键词: Abbreviations; Acetaminophen; Acute; Affect; Agonist; Animals; Atherosclerosis; Bile Acid Biosynthesis Pathway; Bile Acids; Biliary; Biotin; Birds; Cardiovascular Diseases; Catabolism; Cell membrane; ChIP-seq; Chenodeoxycholic Acid; Cholesterol; Cholesterol Homeostasis; Cholic Acids; Chromatin; Clinical Trials; Data; Drug Metabolic Detoxication; Enterohepatic Circulation; Enzymes; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Glutathione S-Transferase; Hepatic; Hepatocyte; Hepatotoxicity; Homeostasis; Homologous Gene; Hyperglycemia; Hyperlipidemia; Inflammation; Inflammatory; Inflammatory Response; Intestines; Liver; Liver diseases; Maintenance; Messenger RNA; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Nuclear Receptors; Oncogenes; Pathway interactions; Permeability; Phase; Physiological; Physiology; Plasma; Predisposition; Receptor Activation; Regulation; Relative (related person); Repression; Resistance; Response Elements; Rodent; Role; Signal Pathway; Signal Transduction; Testing; Text; Toxin; Transcription Repressor/Corepressor; base; cancer type; fibrosarcoma; gain of function; gene function; genome wide association study; genome-wide analysis; hepatotoxin; improved; lipid metabolism; loss of function; novel; overexpression; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Activation of the farnesoid-X-nuclear receptor (FXR) induces the transcription of numerous genes that affect the regulation of multiple metabolic pathways. The importance of FXR in normal physiology can be seen in animals where dysregulation of FXR has been shown to be associated with abnormal bile acid metabolism, hyperlipidemia, atherosclerosis, hyperglycemia, increased susceptibility to hepatotoxins, hepatocarcinoma and increased permeability of the intestinal barrier. Despite this plethora of effects, the central role of FXR in regulating virtually all aspects of bile acid metabolism and th enterohepatic circulation is particularly important. The hepatic synthesis of chenodeoxycholic acid (CDCA) and cholic acid (CA) is regulated by the enzymes Cyp7a1 and Cyp8b1, respectively. Numerous studies have supported a model in which activation of hepatic and intestinal FXR results in repression of Cyp7a1 and/or Cyp8b1. Current dogma suggests that repression of these two genes is dependent upon increased levels of SHP in the liver and/or the interaction of intestinally- derived Fgf15/19 with its cognate receptor on the hepatocyte plasma membrane. However, the relative importance of SHP and Fgf15/19, and the mechanisms involved in acute or long-term repression of Cyp7a1 and Cyp8b1 remains to be established. Indeed, the current data suggest that additional as yet unknown, pathways may also be involved in repression of these two genes. Herein, we identify two novel pathways that are involved in the repression of Cyp7a1 and Cyp8b1. First, we identified two transcriptional repressors as novel FXR target genes. Neither gene was known to be involved in bile acid or lipid metabolism. We then used gain-of-function and loss-of-function studies to demonstrate that these repressors function to repress Cyp8b1 and Cyp7a1, respectively. Importantly, such repression altered the ratios of specific bile acids in the bile acid pool. In addition, we demonstrate the regulation of number of glutathione transferases, and related genes, that function to protect the liver from toxic challenges. Together, these preliminary studies i) challenge the current paradigm that SHP and Fgf15/19 are the major/sole regulators of Cyp7a1 and Cyp8b1 and ii) provide a mechanism that explains the hepato-protection that can result from FXR activation. The proposed experiments will extend these novel findings and identify the molecular mechanisms involved. A better understanding of the effects of FXR activation appears particularly important, as FXR agonists are currently being tested in clinical trials.

描述（由申请人提供）：法尼醇-X-核受体（FXR）的激活诱导影响多种代谢途径调节的众多基因的转录。 FXR 在正常生理学中的重要性可以从动物身上看出，其中 FXR 失调已被证明与异常胆汁酸代谢、高脂血症、动脉粥样硬化、高血糖、对肝毒素、肝癌和肠屏障通透性增加的敏感性增加有关。尽管有如此多的作用，FXR 在调节胆汁酸代谢和肠肝循环的几乎所有方面的核心作用尤其重要。鹅去氧胆酸 (CDCA) 和胆酸 (CA) 的肝脏合成分别由酶 Cyp7a1 和 Cyp8b1 调节。大量研究支持了一种模型，其中肝脏和肠道 FXR 的激活会导致 Cyp7a1 和/或 Cyp8b1 的抑制。目前的教条表明，这两个基因的抑制取决于肝脏中 SHP 水平的增加和/或肠源性 Fgf15/19 与其肝细胞质膜上的同源受体的相互作用。然而，SHP 和 Fgf15/19 的相对重要性以及参与急性或长期抑制 Cyp7a1 和 Cyp8b1 的机制仍有待确定。事实上，目前的数据表明，其他未知的途径也可能参与这两个基因的抑制。在此，我们确定了参与 Cyp7a1 和 Cyp8b1 抑制的两条新途径。首先，我们确定了两个转录抑制子作为新的 FXR 靶基因。已知这两个基因均不参与胆汁酸或脂质代谢。然后，我们使用功能获得和功能丧失研究来证明这些阻遏蛋白分别具有抑制 Cyp8b1 和 Cyp7a1 的功能。重要的是，这种抑制改变了胆汁酸库中特定胆汁酸的比例。此外，我们还证明了谷胱甘肽转移酶和相关基因数量的调节，其功能是保护肝脏免受毒性挑战。总之，这些初步研究 i) 挑战了当前的范式，即 SHP 和 Fgf15/19 是 Cyp7a1 和 Cyp8b1 的主要/唯一调节因子，ii) 提供了一种机制来解释 FXR 激活可能产生的肝脏保护作用。拟议的实验将扩展这些新发现并确定所涉及的分子机制。更好地了解 FXR 激活的影响显得尤为重要，因为 FXR 激动剂目前正在临床试验中进行测试。