The AHR-FGF221 Axis in Hepatic Steatosis and Metobolic Syndrome

 描述(申请人提供)：芳香烃受体(AHR)，在肝脏中高表达，最初被定义为一种调节异生代谢的异生受体。随后的研究表明，AhR还通过影响生理和组织发育而具有内生功能。在之前的资助期间，我们已经证明了AhR的激活导致了自发性脂肪肝，并使小鼠对甲硫酮和胆碱缺乏饮食诱导的非酒精性脂肪性肝炎致敏。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，在很大程度上仍不清楚。成纤维细胞生长因子21(FGF21)主要在肝脏产生，是一种全身性胰岛素增敏剂。FGF21表现出许多代谢益处，从减轻体重到缓解高血糖和胰岛素抵抗，以及改善血脂状况。尽管FGF21被证明受AHR激动剂TCDD的调节，但这种调节的病理生理学相关性仍有待确定。我们的初步结果表明：1)四环素诱导的转基因小鼠在肝脏中表达人AHR(CA-AHR)；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；3)尽管转基因针对肝脏，但CA-AHR转基因小鼠在肝外组织中表现出代谢优势，如脂肪组织和骨骼肌；4)AHR激活的多效性与FGF21的诱导有关，而FGF21的腺病毒敲除取消了CA-AHR转基因基因的代谢优势；5)FGF21是AHR的转录靶点；6)内源性AhR激动剂6-甲酰吲哚并[3，2-b]咔唑(FICZ)可有效激活AhR；7)CA-AHR转基因小鼠至28周龄未表现出自发性非酒精性脂肪性肝炎(NASH)的迹象；8)CA-AHR转基因小鼠有逆转既有的胰岛素抵抗的趋势。根据我们的初步数据，我们假设“异种受体”AHR通过形成AHR-FGF21信号轴，在调节能量代谢和胰岛素敏感性方面具有以前未知的肝脏功能。具体地说，我们假设AHR的激活可以解除脂肪肝与胰岛素抵抗的关系，并通过转录激活FGF21基因来提供代谢益处。我们提出了三个具体的目标来验证我们的假设：1)确定AHR的药物激活是否提供代谢益处，并将脂肪肝与胰岛素抵抗分开；2)确定AhR的遗传和药物激活是否缓解先前存在的肥胖和胰岛素抵抗；3)确定FGF21是否对AHR的代谢益处是必需的。据我们所知，目前的研究是首次尝试系统地确定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获得性功能模型，可以在不考虑毒性的情况下了解AHR的内生功能。AHR-FGF21轴的内分泌信号通路将AHR确立为一个关键的环境调节剂，它整合了化学物质暴露的信号，调节了脂质和能量代谢。我们的结果还表明，开发无毒的AHR激动剂可能是管理代谢综合征的一种新方法。

 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.