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。胆汁酸包括鹅去氧胆酸（CDCA）、去氧胆酸（DCA）和石胆酸（LCA）是法尼醇X受体（FXR）的内源性激活剂。此外，结合胆汁酸牛磺-β-鼠胆酸发现由肠道微生物群调节的T-beta-MCA是小鼠中的天然FXR拮抗剂，并且增加的肠道T-beta-MCA水平通过抑制肠道FXR信号传导改善HFD诱导的肥胖、葡萄糖耐受不良和NAFLD。肠FXR恢复HFD破坏的葡萄糖稳态的分子机制知之甚少，并且是当前研究的主题。虽然T-beta-MCA是肝脏中产生的天然FXR拮抗剂，但它在肠道中被胆盐水解酶（BSH）快速水解为β-MCA，导致肠道中的水平过低，无法抑制FXR信号传导。因此，抑制细菌BSH可以通过增加肠道T-β-MCA来阻断肠道FXR信号传导。咖啡酸苯乙酯（CAPE），一种非处方膳食补充剂和细菌BSH抑制剂，增加了肠道T-β-MCA的水平，它选择性地抑制肠道FXR信号传导。肠FXR抑制通过抑制肠回肠上皮细胞中新型FXR靶基因Smpd 3和Sptlc 2的表达来减少神经酰胺。较低的血清神经酰胺介导的肝线粒体乙酰辅酶A水平和丙酮酸羧化酶活性降低，并减弱肝纤维化，独立于体内体重变化和肝胰岛素信号传导;这是逆转与神经酰胺或FXR激动剂GW 4064治疗小鼠。神经酰胺主要通过诱导内质网应激而显著减弱线粒体柠檬酸合酶活性，内质网应激引发肝线粒体乙酰辅酶A水平和丙酮酸羧化酶活性增加。这些结果揭示了膳食补充剂咖啡酸苯乙酯和肠道FXR调节肝脏新生的机制，并表明抑制肠道FXR是治疗高血糖症的策略。另一项研究发现，FXR影响化学诱导的肝毒性。肝毒性是暴露于工业化学品和药物的人类的主要关注点。胆汁酸（BA）代谢的主要调节因子法尼醇X受体（FXR）的破坏可增强毒物暴露后小鼠对肝损伤的敏感性，但其确切机制尚不清楚。在这项研究中，BA代谢，FXR和化学诱导的肝毒性之间的相互关系进行了研究，使用代谢组学，FXR基因敲除小鼠和肝细胞，和腺病毒。单次低剂量腹腔注射四氯化碳（CCl 4），一种小鼠急性肝炎的诱导剂，导致更严重的肝细胞损伤和更高的促炎介质诱导，如趋化因子（C-C基序）配体2（Ccl 2），在Fxr基因敲除小鼠中。血清代谢组学分析显示，在这些小鼠中循环牛磺胆酸盐（TCA）T-β-MCA显著增加，并且在Fxr缺失小鼠中通过腺病毒强制表达胆盐输出蛋白（BSEP）改善了CCl 4诱导的肝损伤。用TCA而不是T-beta-MCA处理Fxr缺失的肝细胞，显著增加了c-Jun-N-末端激酶（JNK）活化和Ccl 2 mRNA水平，并且通过与JNK抑制剂SP 600125共处理减弱了Ccl 2 mRNA的上调，表明TCA直接放大了主要由JNK介导的肝细胞炎症信号传导。此外，用SP 600125预处理或通过使用重组腺病毒恢复肝脏中的FXR表达，减轻CCl 4诱导的肝损伤。总的来说，这些结果表明，TCA-JNK轴可能与FXR缺失小鼠对CCl 4诱导的急性肝损伤的易感性增加有关，并为FXR及其下游基因靶点（如BSEP）保护免受化学诱导的肝毒性的机制提供了线索。合成MCA的酶学尚不清楚。小鼠和大鼠可在6 β位羟基化鹅去氧胆酸（CDCA）形成α- MCA，熊去氧胆酸（UDCA）形成β-MCA。然而，MCA在人类中没有形成到任何可感知的程度，并且这种物种差异的机制尚不清楚。几种Cyp-null小鼠系的比较显示，在Cyp 2c-簇null（Cyp 2c-null）小鼠的肝脏样品中未检测到α-MCA和β-MCA。总体胆汁酸分析进一步显示，在Cyp 2c基因敲除小鼠盲肠和粪便中不存在MCA及其结合衍生物，且CDCA、UDCA浓度较高。重组CYP的分析显示，α-MCA和β-MCA是通过Cyp 2c 70氧化CDCA和UDCA产生的。CYP 2C 9人源化小鼠具有与Cyp 2c缺失小鼠相似的胆汁酸代谢产物，表明人CYP 2C 9不氧化CDCA和UDCA，从而解释了MCA产生的种属差异。由于人类不产生MCA，因此他们缺乏T-beta-MCA，即小鼠中的天然FXR拮抗剂，其调节肥胖、胰岛素抵抗和NAFLD，如上所述

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. Bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA) are endogenous activators of the farnesoid X receptor (FXR). In addition, the conjugated bile acid tauro-beta-muricholic acid (T-beta-MCA), that is modulated by the gut microbiota was found to be a natural FXR antagonist in mice, and increased intestinal T-beta-MCA levels ameliorate HFD-induced obesity, glucose intolerance and NAFLD via inhibition of intestinal FXR signaling However, the molecular mechanism by which intestinal FXR restores HFD-disrupted glucose homeostasis is poorly understood and the subject of the current study. While T-beta-MCA is a natural FXR antagonist produced in liver, it is rapidly hydrolyzed into beta-MCA by bile salt hydrolase (BSH) in the gut, resulting in levels that are too low in the intestine to inhibit FXR signaling. Therefore, inhibition of bacterial BSH could block intestinal FXR signaling by increasing intestinal T-beta-MCA. Caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial BSH, increased levels of intestinal T-beta-MCA, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramides by suppressing expression of the novel FXR target genes Smpd3 and Sptlc2 in intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities, and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase activities. These results reveal a mechanism by which the dietary supplement caffeic acid phenethyl ester and intestinal FXR regulates hepatic gluconeogenesis, and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia. Another study found that FXR influences chemically-induced liver toxicity. Hepatotoxicity is of major concern for humans exposed to industrial chemicals and drugs. Disruption of farnesoid X receptor (FXR), a master regulator of bile acid (BA) metabolism, enhanced the sensitivity to liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. In this study, the interconnection between BA metabolism, FXR, and chemically-induced hepatotoxicity was investigated using metabolomics, Fxr-null mice and hepatocytes, and adenovirus. A single low-dose intraperitoneal injection of carbon tetrachloride (CCl4), an inducer of acute hepatitis in mice, resulted in more severe hepatocyte damage and higher induction of pro-inflammatory mediators, such as chemokine (C-C motif) ligand 2 (Ccl2), in Fxr-null mice. Serum metabolomics analysis revealed marked increases in circulating taurocholate (TCA) T-beta-MCA in these mice, and forced expression of bile salt export protein (BSEP) by adenovirus in Fxr-null mice ameliorated CCl4-induced liver damage. Treatment of Fxr-null hepatocytes with TCA, but not T-beta-MCA, significantly increased c-Jun-N-terminal kinase (JNK) activation and Ccl2 mRNA levels, and up-regulation of Ccl2 mRNA was attenuated by co-treatment with a JNK inhibitor SP600125, indicating that TCA directly amplifies hepatocyte inflammatory signaling mainly mediated by JNK under FXR-deficiency. Additionally, pre-treatment with SP600125 or restoration of FXR expression in liver by use of recombinant adenovirus, attenuated CCl4-induced liver injury. Collectively, these results suggest that the TCA-JNK axis is likely associated with increased susceptibility to CCl4-induced acute liver injury in Fxr-null mice, and provide clues to the mechanism by which FXR and its downstream gene targets, such as BSEP, protects against chemically-induced hepatotoxicity. The enzymology by which MCA is synthesized was not known. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6beta-position to form alpha- MCA, and ursodeoxycholic acid (UDCA) to form beta-MCA). However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known. Comparison of several Cyp-null mouse lines revealed that alpha-MCA and beta-MCA were not detected in the liver samples from Cyp2c-cluster null (Cyp2c-null) mice. Global bile acids analysis further revealed the absence of MCA and their conjugated-derivatives, and high concentration of CDCA, UDCA in Cyp2c-null mouse cecum and feces. Analysis of recombinant CYPs revealed that alpha-MCA and beta-MCA were produced by oxidation of CDCA and UDCA by Cyp2c70. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, indicating that human CYP2C9 does not oxidize CDCA and UDCA thus explaining the species differences in production of MCA. Since humans do not produce MCA, they lack T-beta-MCA, the natural FXR antagonists in mouse, that modulates obesity, insulin resistance and NAFLD as described above