TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.
TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.
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DOI：
10.1096/fj.202101607r
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发表时间：
2022-03
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影响因子：
--
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FGF19/FGF15是肝脏胆盐和脂质代谢的内分泌调节剂，在临床试验中已显示出治疗NASH的良好效果。FGF19/15转录并从小肠肠细胞释放到肠肝循环中，以响应胆汁诱导的FXR激活。此前，FGF19的TSS在结直肠癌细胞中被鉴定为与wnt调控的TCF7L2/编码的转录因子TCF4结合。Wnt信号传导受损及其辅助受体LRP6特异性功能丧失与NASH相关。因此，我们研究了TCF7L2/TCF4是否上调小肠中的Fgf19并通过肠-肝串扰抑制NASH。我们检测了小鼠肠上皮TCF7L2过表达、单倍不足和条件敲除模型。TCF7L2+/−小鼠表现出血浆胆盐和脂质的增加，并发生饮食诱导的脂肪肝疾病，而全球过表达TCF7L2的小鼠则不会出现这些特征。综合体内分析显示，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。因此,VilinCreert2;Tcf7L2fl/fl小鼠回肠Fgf19减少，血浆胆汁增加。在代谢综合征相关的LRP6R611C替代小鼠中，TCF7L2的整体过表达挽救了后者的脂肪肝和纤维化。引人注目的是，在人类NASH中，肝脏TCF4水平降低，CYP7a1水平升高，这表明TCF4依赖性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-肝串扰的上游调节剂的关键作用，该串扰维持胆汁和肝脏甘油三酯的稳态。
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, VilinCreert2; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6R611C 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.
影响因子：
3.7
作者：
Bhat N;Park J;Zoghbi HY;Arthur JS;Zaret KS
通讯作者：
Zaret KS