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: 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
• 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

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受体与酒精性肝病的性二型性。 摘要：酒精性肝病(ALD)是由过量饮酒引起的，在人类和人类中都更为严重。 和雌性啮齿类动物相比，它们的雄性同行。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)的药代动力学、雌激素水平和酒精清除率。然而，准确的 机制(S)还不是很清楚，尽管最近的迹象表明两者都很复杂 ALD性二型性与ALD发病机制例如，小鼠肝脏脂肪特异性的上调 蛋白27(Fsp27)及其人类同源基因--细胞死亡诱导DNA碎片因子α样效应子c (CIDEC)以前被认为与代谢紊乱和细胞凋亡有关，它促进一种 进行性酒精性脂肪性肝炎(ASH)，在小鼠和人类ASH患者中都是如此。然而， 乙醇对女性的肝毒性是否与Fsp27上调有关尚不清楚。FSP27是人类免疫缺陷病毒的靶基因。 生脂转录因子过氧化体增殖物激活受体γ(γ)及其γ的抑制 改善小鼠的灰质。上游，PPARγ受孕烷X受体(PxR)转录调控，a 异种生物核受体，诱导参与药物和其他外来物质解毒的基因 化学制品。我们之前已经证明，小鼠PXR加剧了乙醇诱导的肝毒性。因此， 我们询问人类PXR信号是否类似地调制无水乙醇中的PPARγ-FSP27信号轴 肝毒性，尤其关注ALD的性别差异。出乎意料的是，我们发现慢性+狂欢 乙醇摄入以一种性别依赖的方式上调PPARγ和FSP27 小鼠，缺乏小鼠PXR基因，但携带完整的人PXR基因。此外，核的本构关系 雄烷受体(CAR)和PXR靶基因Cyp2b10是已知的产生活性氧物种的基因。 在喂食乙醇的雌性hPXR小鼠的肝脏中也有增加。因此，我们的中心假设是，女性 HPXR基因介导乙醇肝毒性中的性别二型性通过增加脂肪生成和 增强型Fsp27和Cyp2b10基因协同产生ROS 表情。为了解决这些假设，我们将确定PXR-PPARγ-FSP27的贡献 信号轴到女性特有的ALD病理(目标1)。确定CYP2B6诱导是否为 参与女性特异性乙醇所致的肝毒性(目标2)。确定PXR的贡献， PPARγ、CYP2B6和CIDEC基因多态性与肌萎缩侧索硬化症的性别和种族差异(目标3)。一个 这一提议的优点在于，它利用了人源化的老鼠和两性的人体组织，加快了 应用于临床研究。基于我们强大的初步数据，这项建议将提供有价值的见解 PXR的性别和物种特异性调控如何针对基因以及特定的生物标记物 代谢组学有助于乙醇肝毒性的性别差异，这可能确定治疗靶点 用于治疗酒精性肝病。