Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
World J Gastroenterol. 2023 Jun 7;29(21):3280-3291. doi: 10.3748/wjg.v29.i21.3280.
Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.
To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG).
By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected.
After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed.
Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.
成纤维细胞生长因子 (FGF) 15/19 在回肠远端表达和分泌，可通过内分泌方式调节肝脏的葡萄糖代谢。减肥手术后，胆汁酸 (BA) 和 FGF15/19 的水平均升高。然而，尚不清楚 FGF15/19 的增加是否是由 BAs 诱导的。此外，尚不清楚 FGF15/19 的升高是否有助于减肥手术后肝脏葡萄糖代谢的改善。
研究减肥手术后升高的 BAs 改善肝葡萄糖代谢的机制。
通过计算和比较袖状胃切除术 (SG) 后体重的变化，我们检查了 SG 的减肥效果。口服葡萄糖耐量试验 (OGTT) 试验和 OGTT 曲线下面积用于评估 SG 的抗糖尿病作用。通过检测糖原含量、糖原合酶的表达和活性以及葡萄糖-6-磷酸酶 (G6Pase) 和磷酸烯醇丙酮酸羧激酶 (Pepck)，我们评估了肝糖原含量和糖异生活性。我们检测了手术后第 12 周系统血清和门静脉中总 BA (TBA) 以及法尼醇 X 受体 (FXR)-激动性 BA 亚类的水平。然后检测了回肠 FXR 和 FGF15 以及参与葡萄糖代谢的肝脏 FGF 受体 4 (FGFR4) 的组织学表达及其相关信号通路。
手术后，SG 组的食物摄入量和体重增加减少。SG 后肝糖原含量和糖原合酶活性明显增加，而肝糖异生关键酶：G6Pase 和 Pepck 的表达则受到抑制。SG 后血清和门静脉中的 TBA 水平均升高，血清中 FXR-激动性 BA 亚类：鹅去氧胆酸 (CDCA)、石胆酸 (LCA)，门静脉中 CDCA、DCA、LCA 在 SG 组中均高于 SHAM 组。因此，SG 组回肠 FXR 和 FGF15 的表达也有所提高。此外，SG 手术大鼠肝 FGFR4 的表达受到刺激。结果，其相应的糖原合成途径：FGFR4-Ras-细胞外信号调节激酶途径的活性被刺激，而相应的肝糖异生途径：FGFR4-cAMP 调节元件结合蛋白-过氧化物酶体增殖物激活受体 γ 共激活剂-1α 途径的活性受到抑制。
SG 后升高的 BAs 通过激活其受体 FXR 诱导远端回肠中 FGF15 的表达。此外，促进的 FGF15 部分介导了 SG 对肝脏葡萄糖代谢的改善作用。
