■通过FXR和TGR5信令,胆汁酸(BAs)调节脂质和葡萄糖代谢,炎症和纤维化。因此,肠道分泌后,BAs返回肝脏,修饰和重吸收可能与非酒精性脂肪性肝炎(NASH)的发病机制有关。在这里,我们在NASH的临床前模型中表征了BAs的肠肝谱和信号传导,并探讨了BA成分实验操作的后果。
■我们使用高脂饮食(HFD)喂养的foz/foz和高果糖西方饮食喂养的C57BL/6J小鼠,并将它们与各自的控件进行比较。小鼠接受补充有脱氧胆酸(DCA)的饮食以调节BA组成。
■与对照组相比,NASH小鼠的门静脉血液和胆汁中的BAs浓度较低,而全身BA浓度没有显著改变。值得注意的是,次级BAs的浓度,尤其是DCA,在NASH小鼠的胆汁和门静脉血中,继发性与原发性BA的比例显着降低。因此,门静脉血中FXR和TGR5配体含量低,并在NASH小鼠中赋予较差的抗炎保护。NASH肝脏中增强的一级BA合成和二级BA向一级BA的转化有助于二级BA的消耗。HFD喂养的foz/foz小鼠的膳食DCA补充恢复了门静脉血液中的BA浓度,增加TGR5和FXR信号,改善了代谢异常状态,免受脂肪变性和肝细胞膨胀,减少巨噬细胞浸润。
■肝肠循环中的BA组成,但不是在全身循环中,在NASH的临床前模型中发生了深刻的变化,在二级BA中具有特定的消耗。从NASH保护的BA配置文件的饮食校正,支持肠肝性BA在NASH发病机制中的作用。
■这项研究清楚地表明,在相关的临床前模型中,肝肠胆汁酸的改变极大地促进了非酒精性脂肪性肝炎的发展。的确,胆汁酸组成的实验调节恢复了受干扰的FXR和TGR5信号传导,并预防了非酒精性脂肪性肝炎和相关的代谢紊乱。
UNASSIGNED: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition.
UNASSIGNED: We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition.
UNASSIGNED: Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration.
UNASSIGNED: BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH.
UNASSIGNED: This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.