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: 10659135
• 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/10659135
• 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; Caucasians; Cell Death Induction; 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; 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; 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; pharmacologic; pregnane X receptor; problem drinker; receptor; 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：酒精性肝病中的人类怀孕X受体和性二态性。 摘要：酒精性肝病（ALD）因过量的酒精使用而发展，并且在两个人中都更为严重 和啮齿动物的女性比男性同龄人。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 在乙醇（ETOH）药代动力学中，雌激素水平和饮酒率。但是，精度 机制尚不清楚，尽管最近有一些迹象表明这两者都复杂 ALD性二态性和ALD发病机理。例如，鼠肝脂肪特异性的上调 蛋白27（FSP27）及其人类直系同源，细胞死亡诱导DNA片段化因子α样效应子C （CIDEC）以前与代谢性疾病和细胞凋亡有关，它促进了 小鼠和人类患者的ALD，酒精性脂肪性肝炎（灰）的进行性形式。然而， 雌性中的EtOH肝毒性是否涉及FSP27上调尚不清楚。 FSP27是一个靶基因 脂肪生成转录因子过氧化物体增生剂激活受体γ（PPARγ）和PPARγ的抑制 改善小鼠的灰分。上游，PPARγ受孕妇X受体（PXR）的转录调节，A 诱导参与药物排毒和其他外国排毒基因的异生物核接收器 化学物质。我们以前已经表明，小鼠PXR加剧了eTOH诱导的肝毒性。所以， 我们询问人PXR信号是否类似地调节EtOH中的PPARγ-FSP27信号轴 肝毒性，特别是专注于ALD的性别差异。出乎意料的是，我们发现慢性加薪 EtoH摄入以性别依赖性方式以PXR人性化（HPXR）更新了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，核本构 雄激素受体（CAR）和PXR靶基因CYP2B10，已知会产生活性氧，是 ETOH喂养的雌性HPXR小鼠的生活也增加了。那是我们的中心假设是女性 HPXR基因通过增加脂肪生成和 通过增强的FSP27和CYP2B10基因协同生成活性氧（ROS） 表达。为了解决这些假设，我们将确定PXR-PPARγ-FSP27的贡献 对女性特异性ALD病理学的信号轴（AIM 1）。确定CYP2B6诱导是否是 参与女性特异性ETOH诱导的肝毒性（AIM 2）。确定PXR的贡献， PPARγ，CYP2B6和CIDEC对ALD性别和种族差异的遗传多态性（AIM 3）。一个 该提议的优势是，它利用了男女的人源化小鼠和人类组织，加快 应用于临床研究。根据我们强大的初步数据，该提案将提供宝贵的见解 介绍PXR靶基因的性别和规格特定调节以及来自特定的生物标志物 代谢组学有助于ETOH诱导的肝毒性的性别差异，这可能鉴定出治疗靶标 用于治疗ALD。