The AHR-FGF221 Axis in Hepatic Steatosis and Metobolic Syndrome

肝脂肪变性和代谢综合征中的 AHR-FGF221 轴

• 批准号: 9120589
• 负责人: Wen Xie
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120589
• 关键词: Adipose tissue; Affect; Age; Agonist; Aryl Hydrocarbon Receptor; Body Weight; Carbazoles; Chemical Exposure; Data; Development; Diet; Doxycycline; Endocrine; Energy Metabolism; Exhibits; Extrahepatic; Fatty Liver; Funding; Genes; Genetic; Goals; Hepatic; High Fat Diet; Human; Hyperglycemia; Insulin Resistance; Ligands; Lipids; Liver; Metabolic; Metabolic syndrome; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Physiology; Regulation; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Syndrome; Testing; Tetrachlorodibenzodioxin; Tetracyclines; Tissues; Toxic effect; Transgenes; Transgenic Mice; Xenobiotic Metabolism; Xenobiotics; base; choline deficient diet; feeding; fibroblast growth factor 21; gain of function; insulin sensitivity; insulin sensitizing drugs; knock-down; lipid metabolism; nonalcoholic steatohepatitis; novel strategies; peptide hormone; public health relevance; receptor; toxicant

 DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AHR), highly expressed in the liver, was originally defined as a xenobiotic receptor that regulates xenobiotic metabolism. Subsequent studies suggest that AhR also has endobiotic functions by affecting physiology and tissue development. In the previous funding period, we have shown that activation of AhR caused spontaneous fatty liver and sensitized mice to methione and choline deficient diet- induced nonalcoholic steatohepatitis. However, whether and how AhR affects dietary induced fatty liver and associated metabolic syndrome such as obesity and insulin resistance remains largely unknown. The fibroblast growth factor 21 (FGF21), produced predominantly in the liver, is a systemic insulin sensitizer. FGF21 exhibits many metabolic benefits, ranging from reducing body weight to alleviation of hyperglycemia and insulin resistance, and improvement of lipid profiles. Although FGF21 was shown to be regulated by the AHR agonist TCDD, the pathophysiological relevance of this regulation remains to be defined. Our preliminary results showed that: 1) Tetracycline inducible transgenic mice expressing the constitutively activated human AHR (CA-AHR) in the liver have been created; 2) CA-AHR transgenic mice showed protection from high-fat diet (HFD) induced obesity and insulin resistance despite having severe fatty liver; 3) Although the transgene was targeted to the liver, CA-AHR transgenic mice exhibited metabolic benefits in extrahepatic tissues, such as the adipose tissue and skeletal muscle; 4) The pleiotropic benefit of AHR activation was associated with the induction of FGF21, and adenoviral knockdown of FGF21 abolished the metabolic benefit of the CA-AHR transgene; 5) FGF21 is a transcriptional target of AHR; 6) The endogenous AhR agonist 6-formy-indolo[3,2-b] carbazole (FICZ) activated AhR efficiently; 7) CA-AHR transgenic mice up to 28 weeks of age did not show signs of spontaneous non-alcoholic steatohepatitis (NASH); and 8) The CA-AHR transgene showed a tendency to reverse the pre-existing insulin resistance. Based on our preliminary data, we hypothesize that the "xenobiotic receptor" AHR has a previously unrecognized hepatic function in regulating energy metabolism and insulin sensitivity by forming the AHR-FGF21 signaling axis. Specifically, we hypothesize that activation of AHR disassociates fatty liver from insulin resistance and provides metabolic benefits by transcriptionally activating the FGF21 gene. We propose three specific aims to test our hypotheses: 1) To determine whether pharmacological activation of AHR confers metabolic benefits and disassociates fatty liver from insulin resistance; 2) To determine whether genetic and pharmacological activation of AhR relieves pre-existing obesity and insulin resistance; 3) To determine whether FGF21 is necessary for the metabolic benefit of AHR. To our knowledge, the current study represents the first attempt to systematically determine the role of AhR in diet-induced metabolic abnormalities. The tetracycline inducible human AHR transgenic mice represent a unique gain of function model to understand the endobiotic function of AHR without the concern of the toxicity. The AHR-FGF21 axis of endocrine signaling pathway establishes AHR as a pivotal environmental modifier that integrates signals from chemical exposure in the regulation of lipid and energy metabolism. Our results also suggest that development of non-toxic AHR agonists may be a novel approach in managing metabolic syndrome.

 描述（由申请人提供）：芳香烃受体（AHR）在肝脏中高度表达，最初被定义为调节异生物质代谢的异生物质受体。随后的研究表明，AhR也通过影响生理和组织发育而具有内源性功能。在之前的资助期间，我们已经证明AhR的激活引起自发性脂肪肝，并使小鼠对蛋氨酸和胆碱缺乏饮食诱导的非酒精性脂肪性肝炎敏感。然而，AhR是否以及如何影响饮食诱导的脂肪肝和相关的代谢综合征，如肥胖和胰岛素抵抗，在很大程度上仍然未知。成纤维细胞生长因子21（FGF 21）主要在肝脏中产生，是一种全身性胰岛素增敏剂。FGF 21表现出许多代谢益处，范围从减轻体重到减轻高血糖症和胰岛素抵抗，以及改善脂质分布。虽然FGF 21被证明是由AHR激动剂TCDD调节，这种调节的病理生理相关性仍有待确定。初步结果表明：1）建立了四环素诱导的肝内表达组成型激活的人AHR（CA-AHR）转基因小鼠，2）CA-AHR转基因小鼠对高脂饮食（HFD）诱导的肥胖和胰岛素抵抗具有保护作用，但对严重脂肪肝具有保护作用; 3）虽然转基因是针对肝脏的，但CA-AHR转基因小鼠在肝外组织如脂肪组织和骨骼肌中表现出代谢益处; 4）AHR激活的多效性益处与FGF 21的诱导相关，并且腺病毒敲除FGF 21消除了CA-AHR转基因的代谢益处：5）FGF 21是AHR的转录靶点：6）内源性AhR激动剂6-甲酰-吲哚[3，2-B]咔唑（FICZ）有效地激活AhR; 7）长达28周龄的CA-AHR转基因小鼠未显示自发性非酒精性脂肪性肝炎（NASH）的迹象;和8）CA-AHR转基因显示逆转预先存在的胰岛素抗性的趋势。基于我们的初步数据，我们假设“异生物质受体”AHR具有以前未被认识到的通过形成AHR-FGF 21信号传导轴来调节能量代谢和胰岛素敏感性的肝脏功能。具体来说，我们假设AHR的激活使脂肪肝与胰岛素抵抗分离，并通过转录激活FGF 21基因提供代谢益处。我们提出了三个具体的目标来测试我们的假设：1）确定AHR的药理学激活是否赋予代谢益处并将脂肪肝与胰岛素抵抗分离; 2）确定AhR的遗传和药理学激活是否减轻预先存在的肥胖和胰岛素抵抗; 3）确定FGF 21是否是AHR的代谢益处所必需的。据我们所知，目前的研究代表了第一次尝试系统地确定AhR在饮食诱导的代谢异常中的作用。四环素诱导的人AHR转基因小鼠代表了一种独特的功能获得模型，以了解AHR的内源性功能，而无需担心毒性。内分泌信号通路的AHR-FGF 21轴将AHR确立为关键的环境调节剂，其将来自化学暴露的信号整合到脂质和能量代谢的调节中。我们的研究结果还表明，无毒AHR激动剂的发展可能是一种新的方法在管理代谢综合征。