Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
FASEB J. 2022 Mar;36(3):e22185. doi: 10.1096/fj.202101607R.
FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2 mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, Vilin ; Tcf7L2 mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6 substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.
FGF19/FGF15 是一种内分泌调节物，可调节肝脏胆汁盐和脂质代谢，在临床试验中已显示出对 NASH 的治疗有良好效果。FGF19/15 在小肠的肠细胞中被转录和释放，并响应胆汁诱导的 FXR 激活而进入肠肝循环。先前，FGF19 的 TSS 被鉴定为与结直肠癌细胞中的 Wnt 调节的 TCF7L2/编码转录因子 TCF4 结合。Wnt 信号受损和其核心受体 LRP6 的特异性功能丧失与 NASH 有关。因此，我们研究了 TCF7L2 是否在小肠中上调 Fgf19 并通过肠肝相互作用来抑制 NASH。我们研究了 TCF7L2 在肠上皮细胞中过表达、杂合不足和条件性敲除的小鼠模型。TCF7L2 小鼠表现出血浆胆汁盐和脂质增加，并发展为饮食诱导的脂肪肝疾病，而过表达 TCF7L2 的小鼠则对此类特征具有保护作用。全面的体内分析表明，TCF7L2 转录上调肠道中的 FGF15，导致胆汁合成减少和肠道脂质摄取减少。相应地，Vilin ; Tcf7L2 小鼠的回肠中 Fgf19 减少，血浆胆汁增加。代谢综合征相关 LRP6 替代小鼠中 TCF7L2 的全身性过表达挽救了后者的脂肪肝和纤维化。引人注目的是，人类 NASH 中 TCF4 的肝水平降低，CYP7a1 增加，表明 TCF4 依赖的胆汁合成调节与人类疾病相关。这些研究确定了 TCF4 作为 FGF15 介导的肠肝相互作用的上游调节剂的关键作用，该相互作用维持胆汁和肝甘油三酯的稳态。
