Xenobiotic receptors

代谢性疾病包括肥胖、2型糖尿病（胰岛素抵抗）和非酒精性脂肪肝（NAFLD）。这些疾病与心血管疾病（如动脉粥样硬化和非酒精性脂肪性肝炎（NASH））和癌症的风险增加有关。根据癌症类型，与肥胖和胰岛素抵抗相关的癌症风险显着增加超过35%。NAFLD和NASH与肝癌风险显著增加相关。能量摄入和能量消耗之间的长期不平衡导致肥胖，对此没有安全有效的药物治疗。减肥手术，如Roux-en-Y胃旁路术和垂直袖状胃切除术，是治疗肥胖症最有效的手术。经常对中枢神经系统起作用的口服药物的使用与不良副作用有关。肠脂肪阻断剂也会引起不良反应。法尼醇X受体（Farnesoid X receptor，FXR，NR 1H 4）是核受体超家族成员，是胆汁酸、脂类和葡萄糖代谢的重要感受器和调节因子。FXR通过调节胆汁酸在肝脏中的合成和转运以及胆汁酸在回肠中的转运来控制胆汁酸的肠肝循环。在FXR基因敲除小鼠中的研究进一步揭示了这种受体在控制代谢疾病中的重要作用。FXR在肝、肠、脂肪组织和肾的代谢功能障碍的发病机制中具有复杂的作用，并且可以对代谢产生不同的影响。FXR被证明是治疗胆汁淤积的有效药物靶点。发现FXR激动剂奥贝胆酸在小鼠疾病模型中改善脂肪肝和胆汁淤积。奥贝胆酸最近被批准用于治疗原发性胆汁性胆管炎（PBC），尽管副作用包括瘙痒增加和血清胆固醇和脂质升高。抑制肠道FXR已成为控制代谢性疾病的新手段。最近的研究表明，用肠道微生物群修饰剂tempol或抗生素治疗高脂饮食（HFD）肥胖的小鼠，可以抑制肠道FXR信号传导，改善肥胖，胰岛素抵抗和NAFLD。肠道微生物群tempol或抗生素的改变导致发现FXR的天然内源性拮抗剂牛磺酸-β-鼠胆酸（T-beta-MCA），其在肝脏中产生，但通过胆盐水解酶（BSH）被肠道细菌水解。然而，由于细菌BSH，T-β-MCA在未用tempol或杀死表达BSH的细菌的抗生素处理的正常小鼠的肠中不稳定。这些研究导致以下假设：HFD处理的小鼠中FXR的拮抗作用改善了HFD诱导的肥胖、胰岛素抵抗和NAFLD。这些研究发现了一种新的口服小分子甘氨酸特异性FXR抑制剂，甘氨酸-β-鼠胆酸（Gly-MCA），这是一种不水解BSH的胆汁酸，因此在肠道中稳定。以低剂量每天一次口服给予小鼠Gly-MCA预防和治疗饮食诱导的和遗传性（瘦素缺乏小鼠）肥胖症，沿着胰岛素抵抗和NAFLD，而没有全身、肝或肠毒性。进一步的研究表明，特异性抑制一种新的肠道FXR-神经酰胺轴产生显着的代谢改善后，甘油-MCA治疗。机制研究进一步揭示，FXR调节参与神经酰胺合成的基因，神经酰胺介导Gly-MCA的代谢作用。已知血清神经酰胺增加与啮齿动物和人类的代谢疾病相关。神经酰胺注射到Gly-MCA处理的小鼠逆转了Gly-MCA的理想代谢作用。特异性抑制肠道FXR可能是治疗人类代谢紊乱的合理治疗策略。最后，一项人类研究显示，肥胖与回肠中FXR表达和信号传导增加呈正相关。这些研究已经导致在国内和国际上申请了使用方法和Gly-MCA及其相关衍生物的专利，目前正在进行谈判，以将这项技术许可给私营部门用于药物开发。

Metabolic diseases include obesity type 2 diabetes mellitus (insulin resistance) and non-alcoholic fatty liver disease (NAFLD). These disorders are associated with increased risk for cardiovascular diseases such as atherosclerosis and non-alcoholic steatohepatitis (NASH), and cancer. There is a marked increase in cancer risk of over 35% depending on the cancer type, associated with obesity, and insulin resistance. NAFLD and NASH are associated with markedly increased risk for liver cancer. A chronic imbalance between energy intake and energy expenditure causes obesity for which there is no safe and effective drug therapy. Bariatric surgery, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are among the most effective surgical treatments for obesity. The use of oral medications that frequently work on the central nervous system are associated with untoward side effects. Intestinal fat blocking agents also cause adverse effects. Farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of transcription factors, is an important sensor and regulator of bile acid, lipid, and glucose metabolism. FXR controls enterohepatic circulation of bile acids through the regulation of bile acid synthesis and transport in the liver, and and bile acid transport in the ileum. Studies in FXR knockout mice have further revealed the important role of this receptor in the control of metabolic disease. FXR has complex roles in the pathogenesis of metabolic dysfunction in liver, intestine, adipose tissue, and kidney, and can exert different effects on metabolism. FXR was demonstrated to be an effective drug target to treat cholestasis. The FXR agonist obeticholic acid was found to improve fatty liver and cholestasis in mouse disease models. Obeticholic acid was recently approved for the treatment of Primary Biliary Cholangitis (PBC), although side effects include increased pruritus and elevated serum cholesterol and lipids. Inhibition of intestine FXR has emerged as a novel means to control metabolic disease. Recent studies in which mice made obese on a high-fat diet (HFD) were treated with the gut microbiota modifying agent tempol or antibiotics, revealed inhibition of intestinal FXR signaling and amelioration of obesity, insulin resistance and NAFLD. Alteration of the gut microbiota tempol or antibiotics led to the discovery of an natural endogenous antagonist of FXR, taurine-beta-muricholic acid (T-beta-MCA) which is produced in the liver but subjected to hydrolysis by gut bacteria through bile salt hydrolase (BSH). However, due to bacterial BSH, T-beta-MCA was unstable in the intestine of normal mice not treated with tempol or antibiotics which killed bacterial expressing BSH. These studies led to the hypothesis that antagonism of FXR in HFD-treated mice ameliorated HFD-induced obesity, insulin resistance and NAFLD. These studies led to the discovery of a new orally available, small molecule, intestine-specific FXR inhibitor, glycine-beta-muricholic acid (Gly-MCA), a bile acid that is not hydrolyzed BSH and thus stable in the intestine. Oral administration of Gly-MCA to mice at low dose once per day prevents and treats diet-induced and genetic (leptin-deficient mice) obesity, along with insulin resistance and NAFLD without systemic, hepatic or intestinal toxicities. Further studies revealed that specific inhibition of a novel intestinal FXR-ceramide axis produced striking metabolic improvement after Gly-MCA treatment. Mechanistic studies further revealed that FXR regulates genes involved in ceramide synthesis and that ceramides mediate the metabolic effects of Gly-MCA. Increased serum ceramides are known to be associated with metabolic disease in rodents and humans. Injection of ceramides to Gly-MCA-treated mice reversed the desirable metabolic effects of Gly-MCA. Specific inhibition of intestinal FXR may be a reasonable therapeutic strategy for treatment of human metabolic disorders. Finally, a study in humans revealed that obesity was positively correlated with increased FXR expression and signaling in the ileum. These studies have resulted in patents that have been filed nationally and internationally for method of use and for Gly-MCA and related derivatives, and negotiations are underway to license this technology to the private sector for drug development.