Human pregnane X receptor and sexual dimorphism in alcoholic liver disease

人类孕烷X受体与酒精性肝病中的性别二态性

基本信息

批准号：
10100621
负责人：
Maxwell Afari Gyamfi
金额：
$ 33.3万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10100621
关键词：
AODR mortality Acetaldehyde Address Affect African American Alcohol consumption Alcoholic Liver Diseases Alcoholic steatohepatitis Alcohols Alleles Animal Model Apoptosis Biological Assay Blood Blood specimen CYP2B6 gene Caucasians Cell Death Cells Chemicals Chronic Clinical Research DNA Fragmentation DNA Library Data Death Rate Development Disease Dose Drug Kinetics Drug Metabolic Detoxication Estrogens Ethanol Ethanol Metabolism Expression Profiling Fatty acid glycerol esters Female Gene Expression Gene Frequency Generations Genes Genetic Polymorphism Genetic Transcription Genomic DNA Genotype Hepatic Hepatocyte Hepatotoxicity Homologous Gene Human Intervention Intestines Knockout Mice Lipids Liver Mediating Messenger RNA Metabolic Metabolic Diseases Modeling Mus Nuclear Nuclear Receptors Orthologous Gene PPAR gamma Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Pharmacology Production Proteins Reactive Oxygen Species Receptor Gene Receptor Signaling Regulation Reporting Rodent Role Sex Differences Signal Transduction Single Nucleotide Polymorphism Testing Tissues Up-Regulation Variant Wild Type Mouse Woman Xenobiotics alcohol exposure base clinically relevant constitutive androstane receptor diagnostic biomarker disorder risk ethnic difference feeding human tissue humanized mouse insight lipid biosynthesis liver injury male men metabolomics mouse model novel novel diagnostics pregnane X receptor problem drinker sex sexual dimorphism small hairpin RNA specific biomarkers therapeutic target transcription factor

项目摘要

Title: Human pregnane X receptor and sexual dimorphism in alcoholic liver disease. Abstract: Alcoholic liver disease (ALD) develops from excessive alcohol use and is more severe in both human and rodent females than their male counterparts. Female alcoholics also have higher death rate than men. Several mechanisms have been proposed to account for more severe ALD in females, including sex differences in ethanol (EtOH) pharmacokinetics, estrogen levels, and alcohol elimination rates. However, the precise mechanism(s) is/are not well understood, although there are recent indications that suggest complexities in both ALD sexual dimorphism and ALD pathogenesis. For example, the upregulation of murine hepatic fat-specific protein 27 (Fsp27) and its human ortholog, cell death-inducing DNA fragmentation factor alpha-like effector c (CIDEC), which have been previously implicated in metabolic disorders and cell apoptosis, promote a progressive form of ALD, alcoholic steatohepatitis (ASH) in both mice and human patients with ASH. However, whether EtOH hepatotoxicity in females involves Fsp27 upregulation is unknown. FSP27 is a target gene of the lipogenic transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and inhibition of PPARγ ameliorates ASH in mice. Upstream, PPARγ is transcriptionally regulated by pregnane X receptor (PXR), a xenobiotic nuclear receptor that induces genes involved in the detoxification of drugs and other foreign chemicals. We have previously shown that mouse PXR exacerbates EtOH-induced hepatotoxicity. Therefore, we asked whether human PXR signaling similarly modulates the PPARγ-FSP27 signaling axis in EtOH hepatotoxicity, particularly, focusing on sex differences in ALD. Unexpectedly, we found that chronic-plus-binge EtOH ingestion upregulated both PPARγ and FSP27 in a sex-dependent manner in a PXR-humanized (hPXR) mice, lacking the mouse Pxr gene, but carrying the full human PXR gene. Furthermore, the nuclear constitutive androstane receptor (CAR) and PXR target gene, Cyp2b10, known to generate reactive oxygen species, was also increased in the livers of EtOH-fed female hPXR mice. Thus, our central hypothesis is that the female hPXR gene mediates sexual dimorphism in EtOH hepatotoxicity via increased lipogenesis and synergistic generation of reactive oxygen species (ROS) by enhanced Fsp27 and Cyp2b10 gene expression. To address these hypotheses, we will determine the contribution of the PXR-PPARγ-FSP27 signaling axis to female-specific ALD pathology (Aim 1). determine whether CYP2B6 induction is involved in female-specific EtOH-induced hepatotoxicity (Aim 2). determine the contribution of PXR, PPARγ, CYP2B6, and CIDEC genetic polymorphisms to sex and ethnic differences in ALD (Aim 3). A strength of this proposal is that, it makes use of humanized mice and human tissues from both sexes, expediting application to clinical studies. Based on our strong preliminary data, this proposal will provide valuable insights into how sex and species-specific regulation of PXR target genes, as well as specific biomarkers from metabolomics contribute to sex difference in EtOH-induced hepatotoxicity, which may identify therapeutic targets for the treatment of ALD.

标题：人类孕烷 X 受体和酒精性肝病中的性别二态性。摘要：酒精性肝病（ALD）是由过量饮酒引起的，并且在人类中更为严重。与啮齿类动物相比，女性酗酒者的死亡率也高于男性。已经提出了几种机制来解释女性更严重的 ALD，包括性别差异然而，乙醇（EtOH）的药代动力学、雌激素水平和酒精消除率的精确度。尽管最近有迹象表明这两种机制都很复杂，但人们对机制还没有很好地理解 ALD 性别二态性和 ALD 发病机制例如，小鼠肝脏脂肪特异性的上调。蛋白 27 (Fsp27) 及其人类直系同源物、细胞死亡诱导 DNA 碎片因子 α 样效应子 c （CIDEC）先前已被认为与代谢紊乱和细胞凋亡有关，可促进然而，小鼠和人类酒精性脂肪性肝炎 (ASH) 的进展形式。 EtOH 对女性的肝毒性是否涉及 Fsp27 上调尚不清楚。脂肪生成转录因子过氧化物酶体增殖物激活受体 γ (PPARγ) 和 PPARγ 的抑制改善小鼠的 ASH。上游，PPARγ 受孕烷 X 受体 (PXR) 的转录调节。异生核受体，诱导参与药物和其他外来物质解毒的基因我们之前已经表明，小鼠 PXR 会加重乙醇引起的肝毒性。我们询问人类 PXR 信号传导是否类似地调节 EtOH 中的 PPARγ-FSP27 信号传导轴肝毒性，特别是关注 ALD 中的性别差异，我们意外地发现慢性加暴饮暴食。在 PXR 人源化 (hPXR) 中，EtOH 摄入以性别依赖性方式上调 PPARγ 和 FSP27 小鼠，缺乏小鼠 Pxr 基因，但携带完整的人类 PXR 基因此外，还具有核组成型。雄甾烷受体 (CAR) 和 PXR 靶基因 Cyp2b10，已知会产生活性氧，饲喂 EtOH 的雌性 hPXR 小鼠的肝脏也有所增加，因此，我们的中心假设是雌性小鼠。 hPXR 基因通过增加脂肪生成和介导 EtOH 肝毒性中的性别二态性通过增强的 Fsp27 和 Cyp2b10 基因协同产生活性氧 (ROS) 为了解决这些假设，我们将确定 PXR-PPARγ-FSP27 的贡献。女性特有的 ALD 病理学信号轴（目标 1）确定 CYP2B6 诱导是否有效。参与女性特异性 EtOH 诱导的肝毒性（目标 2），确定 PXR 的贡献， PPARγ、CYP2B6 和 CIDEC 基因多态性对 ALD 的性别和种族差异的影响（目标 3）。该提案的优势在于，它利用了两性的人源化小鼠和人体组织，加快了基于我们强有力的初步数据，该提案将提供有价值的见解。研究如何对 PXR 靶基因进行性别和物种特异性调控，以及来自不同物种的特定生物标志物代谢组学有助于乙醇诱导的肝毒性的性别差异，这可以确定治疗靶点用于治疗 ALD。