Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands.
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands.
Int J Mol Sci. 2023 Feb 18;24(4):4132. doi: 10.3390/ijms24044132.
Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well as lipid and glucose homeostasis. Several studies have suggested a role of FXR in the control of genes regulating intestinal glucose handling. We applied a novel dual-label glucose kinetic approach in intestine-specific FXR mice (iFXR-KO) to directly assess the role of intestinal FXR in glucose absorption. Although iFXR-KO mice showed decreased duodenal expression of hexokinase 1 () under obesogenic conditions, the assessment of glucose fluxes in these mice did not show a role for intestinal FXR in glucose absorption. FXR activation with the specific agonist GS3972 induced , yet the glucose absorption rate remained unaffected. FXR activation increased the duodenal villus length in mice treated with GS3972, while stem cell proliferation remained unaffected. Accordingly, iFXR-KO mice on either chow, short or long-term HFD feeding displayed a shorter villus length in the duodenum compared to wild-type mice. These findings indicate that delayed glucose absorption reported in whole-body FXR mice is not due to the absence of intestinal FXR. Yet, intestinal FXR does have a role in the small intestinal surface area.
胆汁酸促进膳食脂质的肠道吸收，并作为代谢稳态维持的信号分子发挥作用。法尼醇 X 受体 (FXR) 是一种胆汁酸反应性核受体，参与胆汁酸代谢以及脂质和葡萄糖稳态的调节。多项研究表明，FXR 在调节肠道葡萄糖处理的基因控制中发挥作用。我们在肠道特异性 FXR 敲除小鼠 (iFXR-KO) 中应用了一种新型的双标记葡萄糖动力学方法，直接评估肠道 FXR 在葡萄糖吸收中的作用。尽管 iFXR-KO 小鼠在肥胖条件下十二指肠中己糖激酶 1 () 的表达减少，但对这些小鼠葡萄糖通量的评估并未显示肠道 FXR 在葡萄糖吸收中的作用。用特异性激动剂 GS3972 激活 FXR 诱导了 ，但葡萄糖吸收率保持不变。FXR 激活增加了用 GS3972 治疗的小鼠十二指肠的绒毛长度，而干细胞增殖不受影响。因此，与野生型小鼠相比，无论是在标准饮食、短期还是长期高脂肪饮食喂养的 iFXR-KO 小鼠，其十二指肠中的绒毛长度更短。这些发现表明，全身性 FXR 敲除小鼠中报道的葡萄糖吸收延迟不是由于肠道 FXR 的缺失。然而，肠道 FXR 确实在小肠表面积中起作用。
