Xenobiotic receptors

最近对小鼠的研究报道，肠道菌群的改变改变了宿主胆汁酸的组成，特别是牛磺酸缀合胆汁酸的改变，可以拮抗肠道FXR，并可能引起代谢功能障碍，包括肥胖和胰岛素抵抗。胆汁酸还可以通过激活肝脏FXR和非实质细胞中表达的g蛋白偶联受体TGR5来影响NAFLD。然而，关于肠道菌群、胆汁酸、肠道和肝脏FXR信号在肝脂肪变性发病机制中的作用仍然存在疑问。在本研究中，小鼠被喂食高脂肪饮食（HFD）诱导NAFLD。采用杆菌肽、新霉素和链霉素（BNS）联合杀灭肠道微生物群的某些成员，或采用特异性调节肠道微生物群的临时治疗来确定肠道微生物群在NAFLD发病机制中的作用。使用肠道特异性Fxr-null （FxrdIE）小鼠来阐明肠道微生物群促进NAFLD的机制。FXR在NAFLD中的关键作用是通过使用肠道特异性FXR缺失的小鼠，与野生型小鼠相比，FXR减少了hfd诱导的肝脏甘油三酯积累，部分原因是神经酰胺合成基因的表达受到抑制，导致循环神经酰胺减少。对饲喂hfd的野生型小鼠进行Tempol和抗生素治疗也降低了回肠和血清神经酰胺的水平。较低的血清神经酰胺下调肝脏SREBP1C和CIDEA的表达，导致新生脂肪生成减少。饲喂hfd的小鼠服用C16:0神经酰胺逆转了抗生素治疗对肝脏SREBP1C-CIDEA信号和脂肪变性的抑制。这些研究表明，肠道fxr -神经酰胺轴的抑制介导了肠道微生物群相关的NAFLD发展，并揭示了微生物群、核受体信号传导和NAFLD之间的机制联系。这项工作表明，抑制肠道FXR是治疗NAFLD的一个治疗靶点。FGF21在蛋氨酸和胆碱缺乏饮食诱导的NASH早期的作用：FGF21是一种能量稳态调节剂，在人NAFLD和饲喂蛋氨酸和胆碱缺乏饮食（MCD）后增加，MCD是小鼠非酒精性脂肪性肝炎（NASH）的常规诱导性物质。然而，FGF21诱导在mcd诱导的NASH发生中的意义仍未确定。C57BL/6J fgf21缺失型和野生型小鼠给予MCD治疗1周。肝Fgf21 mRNA在开始MCD治疗后早期升高，不依赖ppar和FXR。虽然两种基因型在白色脂肪分解方面没有显著差异，但fgf21缺失小鼠的肝脏甘油三酯（TG）含量增加，可能是由于编码CD36和磷脂酸磷酸酶2a/2c的基因上调，分别参与脂肪酸摄取和二酰基甘油合成，以及编码肉毒碱棕榈酰辅酶a转移酶1α、PPARgamma共激活因子1α和脂肪TG脂肪酶的mrna增加受到抑制。它们与肝脏的脂质清除有关。mcd处理的fgf21缺失小鼠显示肝内质网（ER）应激增加。原代肝细胞暴露于棕榈酸后，DNA损伤诱导转录本3（内质网应激指标）和FGF21的mRNA编码水平以不依赖ppar的方式升高，表明脂质诱导内质网应激可增强肝脏FGF21的表达。总的来说，FGF21在mcd诱导的NASH的早期阶段升高，可能会减少肝脏脂质积累和随后的内质网应激。这些结果提供了FGF21在NAFLD/NASH中如何增加的可能机制：FGF21在蛋氨酸和胆碱缺乏饮食诱导的NASH早期的作用：由于过量的卡路里摄入和久坐不动的生活方式，多余的脂质储存在肝细胞中，这种情况被称为肝脂肪变性或NAFLD。NASH也可能由NAFLD发展而来，通过增加肝脏炎症和/或肝细胞损伤到脂肪变性肝，导致肝纤维化、肝细胞癌，最终死亡。采用NASH的MCD模型探讨NASH的发病机制及FGF21的作用。FGF21是一种能量稳态调节剂，在人NAFLD中增加。Fgf21 mRNA和血清Fgf21在人NAFLD中升高，并与脂肪变性程度相关，但Fgf21在脂肪变性肝细胞中的诱导机制及其在肝脂肪变性中的作用尚不清楚。C57BL/6J fgf21缺失型和野生型小鼠给予MCD治疗1周。肝Fgf21 mRNA在开始MCD治疗后早期升高，不依赖ppar和FXR。虽然两种基因型在白色脂肪分解方面没有显著差异，但fgf21缺失小鼠的肝脏甘油三酯（TG）含量增加，可能是由于编码CD36和磷脂酸磷酸酶2a/2c的基因上调，分别参与脂肪酸（FA）摄取和二酰基甘油合成，以及编码肉毒碱棕榈酰辅酶a转移酶1α、PPARgamma共激活因子1α和脂肪TG脂肪酶的mrna增加受到抑制。它们与肝脏的脂质清除有关。mcd处理的fgf21缺失小鼠显示肝内质网（ER）应激增加。原代肝细胞暴露于棕榈酸后，DNA损伤诱导转录本3（内质网应激指标）和FGF21的mRNA编码水平以不依赖ppar的方式升高，表明脂质诱导内质网应激可增强肝脏FGF21的表达。总的来说，FGF21在mcd诱导的NASH的早期阶段升高，可能会减少肝脏脂质积累和随后的内质网应激。这些结果提供了FGF21在NAFLD/NASH中增加的可能机制。脂肪细胞对脂肪特异性蛋白27的特异性破坏导致高脂肪饮食喂养小鼠的肝纤维化和胰岛素抵抗：白色脂肪组织（WAT）作为能量库，多余的循环脂肪酸被转运到WAT，转化为甘油三酯，并作为单眼脂滴储存。脂肪特异性蛋白27 （FSP27，人类中的CIDEC）是一种在成熟白色脂肪细胞中高度表达的脂质涂层蛋白，有助于单眼脂滴的形成。然而，脂肪组织中FSP27对全身能量稳态的影响尚不清楚。使用aP2-Cre转基因和Cre/LoxP系统生成脂肪细胞特异性破坏Fsp27基因（Fsp27dAd）的小鼠。在高脂肪饮食喂养下，Fsp27dAd小鼠对体重增加有抵抗力。在这些小鼠的小WAT中，含有多室脂滴的小脂肪细胞分散。与Fsp27（F/F）小鼠相比，Fsp27dAd小鼠分离的脂肪细胞中与线粒体丰度和棕色脂肪细胞特性相关的基因表达水平升高，基础脂肪分解活性显著增强。Fsp27dAd脂肪细胞的脂肪储存功能受损以及由此产生的WAT脂质溢出导致高脂饮食处理的Fsp27dAd小鼠出现明显的肝纤维化、血脂异常和全身性胰岛素抵抗。这些结果表明，FSP27在WAT中储存多余脂肪的关键作用，最大限度地减少导致胰岛素抵抗型糖尿病和非酒精性脂肪肝的异位脂肪积累。该小鼠模型可能有助于了解白色脂肪细胞脂肪储存特性的意义和局部FSP27在全身代谢中的作用，以及估计CIDEC突变引起的人类部分脂肪营养不良的发病机制。

Recent studies in mice reported that alteration of the gut microbiota changes host bile acid composition, notably alteration of taurine-conjugated bile acids that can antagonize the intestinal FXR, and could give rise to metabolic dysfunction including obesity and insulin resistance. Bile acids could also influence NAFLD through activation of the hepatic FXR and the G-protein coupled receptor TGR5 expressed in non-parenchymal cells. However, questions remain about the role of the gut microbiota, bile acids, and intestinal and hepatic FXR signaling in the pathogenesis of hepatic steatosis. In the current study, mice were fed a high-fat diet (HFD) to induce NAFLD. A combination of bacitracin, neomycin, and streptomycin (BNS) to kill certain members of the gut microbiota, or tempol treatment to specifically modulate the gut microbiota were employed to determine the role of the gut microbiota in NAFLD pathogenesis. Intestine-specific Fxr-null (FxrdIE) mice were used to elucidate the mechanism by which the gut microbiota contributes to NAFLD. A critical role for FXR in NAFLD was established by use of intestine-specific Fxr-null mice that had reduced HFD-induced hepatic triglyceride accumulation as compared to wild-type mice, due to decreased circulating ceramides that result in part from repressed of expression of ceramide synthesis genes. Tempol- and antibiotic- treatment of HFD-fed wild-type mice also reduced the levels of ileum and serum ceramides. The lower serum ceramides downregulated hepatic SREBP1C and CIDEA expression leading to decreased de novo lipogenesis. Administration of C16:0 ceramide to HFD-fed mice reversed the suppression of hepatic SREBP1C-CIDEA signaling and steatosis found with antibiotic treatment. These studies demonstrate that inhibition of an intestinal FXR-ceramide axis mediates the gut microbiota-associated development of NAFLD and reveals a mechanistic link between the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a therapeutic target for treatment of NAFLD. Role of FGF 21 in the early stage of NASH induced by methionine- and choline-deficient diet: FGF21 is a modulator of energy homeostasis and is increased in human NAFLD and after feeding of methionine- and choline-deficient diet (MCD), a conventional inducer of murine nonalcoholic steatohepatitis (NASH). However, the significance of FGF21 induction in the occurrence of MCD-induced NASH remains undetermined. C57BL/6J Fgf21-null and wild-type mice were treated with MCD for 1week. Hepatic Fgf21 mRNA was increased early after commencing MCD treatment independent of PPARalpha and FXR. While no significant differences in white adipose lipolysis were seen in both genotypes, hepatic triglyceride (TG) contents were increased in Fgf21-null mice, likely due to the up-regulation of genes encoding CD36 and phosphatidic acid phosphatase 2a/2c, involved in fatty acid uptake and diacylglycerol synthesis, respectively, and suppression of increased mRNAs encoding carnitine palmitoyl-CoA transferase 1alpha, PPARgamma coactivator 1alpha, and adipose TG lipase, which are associated with lipid clearance in the liver. The MCD-treated Fgf21-null mice showed increased hepatic endoplasmic reticulum (ER) stress. Exposure of primary hepatocytes to palmitic acid elevated the mRNA levels encoding DNA damage-inducible transcript 3, an indicator of ER stress, and FGF21 in a PPARalpha-independent manner, suggesting that lipid-induced ER stress can enhance hepatic FGF21 expression. Collectively, FGF21 is elevated in the early stage of MCD-induced NASH likely to minimize hepatic lipid accumulation and ensuing ER stress. These results provide a possible mechanism on how FGF21 is increased in NAFLD/NASH Role of FGF 21 in the early stage of NASH induced by methionine- and choline-deficient diet: Due to excess calorie intake and sedentary lifestyle, surplus lipids are stored in hepatocytes, a condition designated as hepatic steatosis or NAFLD as described above. NASH may also develop from NAFLD through increasing hepatic inflammation and/or hepatocyte damage to steatotic liver, leading to hepatic fibrosis, hepatocellular carcinoma, and eventually death. The MCD model of NASH was used to investigate the mechanism of NASH and the role of FGF21. FGF21 is a modulator of energy homeostasis and is increased in human NAFLD. Fgf21 mRNA and serum FGF21 are elevated in human NAFLD and correlated with the degree of steatosis, but the mechanism by which FGF21 is induced in steatotic hepatocytes and its role in hepatic steatosis are not known. C57BL/6J Fgf21-null and wild-type mice were treated with MCD for 1week. Hepatic Fgf21 mRNA was increased early after commencing MCD treatment independent of PPARalpha and FXR. While no significant differences in white adipose lipolysis were seen in both genotypes, hepatic triglyceride (TG) contents were increased in Fgf21-null mice, likely due to the up-regulation of genes encoding CD36 and phosphatidic acid phosphatase 2a/2c, involved in fatty acid (FA) uptake and diacylglycerol synthesis, respectively, and suppression of increased mRNAs encoding carnitine palmitoyl-CoA transferase 1alpha, PPARgamma coactivator 1alpha, and adipose TG lipase, which are associated with lipid clearance in the liver. The MCD-treated Fgf21-null mice showed increased hepatic endoplasmic reticulum (ER) stress. Exposure of primary hepatocytes to palmitic acid elevated the mRNA levels encoding DNA damage-inducible transcript 3, an indicator of ER stress, and FGF21 in a PPARalpha-independent manner, suggesting that lipid-induced ER stress can enhance hepatic FGF21 expression. Collectively, FGF21 is elevated in the early stage of MCD-induced NASH likely to minimize hepatic lipid accumulation and ensuing ER stress. These results provide a possible mechanism on how FGF21 is increased in NAFLD/NASH. Adipocyte-specific disruption of fat-specific protein 27 causes hepatosteatosis and insulin resistance in high-fat diet-fed mice: White adipose tissue (WAT) functions as an energy reservoir where excess circulating fatty acids are transported to WAT, converted to triglycerides, and stored as unilocular lipid droplets. Fat-specific protein 27 (FSP27, CIDEC in humans) is a lipid-coating protein highly expressed in mature white adipocytes that contributes to unilocular lipid droplet formation. However, the influence of FSP27 in adipose tissue on whole-body energy homeostasis remains unclear. Mice with adipocyte-specific disruption of the Fsp27 gene (Fsp27dAd) were generated using an aP2-Cre transgene with the Cre/LoxP system. Upon high-fat diet feeding, Fsp27dAd mice were resistant to weight gain. In the small WAT of these mice, small adipocytes containing multilocular lipid droplets were dispersed. The expression levels of the genes associated with mitochondrial abundance and brown adipocyte identity were increased, and basal lipolytic activities were significantly augmented in adipocytes isolated from Fsp27dAd mice compared with the Fsp27(F/F) counterparts. The impaired fat-storing function in Fsp27dAd adipocytes and the resultant lipid overflow from WAT led to marked hepatosteatosis, dyslipidemia, and systemic insulin resistance in high-fat diet-treated Fsp27dAd mice. These results demonstrate a critical role for FSP27 in the storage of excess fat in WAT with minimizing ectopic fat accumulation that causes insulin-resistant diabetes and non-alcoholic fatty liver disease. This mouse model may be useful for understanding the significance of fat-storing properties of white adipocytes and the role of local FSP27 in whole-body metabolism and estimating the pathogenesis of human partial lipodystrophy caused by CIDEC mutations.