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

• 批准号: 10443826
• 负责人: Maxwell Afari Gyamfi
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443826
• 关键词: AODR mortality; Acetaldehyde; Address; Affect; African American population; 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; 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

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：酒精性肝病中的人胆固醇X受体和性二型性。 翻译后摘要：酒精性肝病（ALD）的发展，从过度饮酒，是更严重的，在人类和 和啮齿类动物的女性比男性。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 乙醇（EtOH）中的药代动力学、雌激素水平和酒精消除率。然而，精确 机制尚未得到充分理解，尽管最近有迹象表明， ALD性二型性和ALD发病机制。例如，上调鼠肝脂肪特异性 蛋白27（Fsp 27）及其人类直系同源物，细胞死亡诱导DNA片段化因子α样效应子c （CIDEC），以前已经涉及代谢紊乱和细胞凋亡，促进了细胞凋亡。 在患有酒精性脂肪性肝炎（ASH）的小鼠和人类患者中，研究了ALD的进行性形式。然而，在这方面， 雌性中的EtOH肝毒性是否涉及Fsp 27上调尚不清楚。FSP 27是一个靶基因， 脂质生成转录因子过氧化物酶体增殖物激活受体γ（PPARγ）及其抑制 改善小鼠的ASH。在上游，PPARγ受α-羟色胺X受体（PXR）的转录调控， 外源性核受体，诱导参与药物和其他外源性物质解毒的基因 化学品我们以前已经表明，小鼠PXR加重EtOH诱导的肝毒性。因此，我们认为， 我们想知道人类PXR信号传导是否类似地调节EtOH中的PPARγ-FSP 27信号传导轴 肝毒性，特别是关注ALD的性别差异。出乎意料的是，我们发现慢性加狂欢 在PXR人源化（hPXR）细胞中，EtOH摄入以性别依赖的方式上调了PPARγ和FSP 27。 小鼠，缺乏小鼠Pxr基因，但携带完整的人类PXR基因。此外，核结构 雄烷受体（CAR）和PXR靶基因Cyp 2b 10，已知产生活性氧， 在喂食EtOH的雌性hPXR小鼠的肝脏中也有所增加。因此，我们的中心假设是， hPXR基因通过增加脂肪生成介导EtOH肝毒性中的性二态性， 增强Fsp 27和Cyp 2b 10基因协同产生活性氧 表情为了解决这些假设，我们将确定PXR-PPARγ-FSP 27的贡献。 信号传导轴与女性特异性ALD病理学的关系（目的1）。确定CYP 2B 6诱导是否 参与雌性特异性EtOH诱导的肝毒性（目的2）。确定PXR的贡献， PPARγ、CYP 2B 6和CIDEC遗传多态性与ALD的性别和种族差异（目的3）。一 该建议的优点在于，它利用了来自两性的人源化小鼠和人体组织， 应用于临床研究。基于我们强有力的初步数据，这一提议将提供有价值的见解 PXR靶基因的性别和物种特异性调节，以及来自 代谢组学有助于EtOH诱导的肝毒性的性别差异，这可能会确定治疗靶点 用于治疗ALD。