Farnesoid X receptor is inhibited after ileum transposition in diabetic rats: its hypoglycemic effect

Abstract

Background: Aim to investigate bile acid profile changes and the Farnesoid X receptor (FXR) status after ileotransposition (IT), and reveal its possible hypoglycemic mechanism. Methods: Twenty male diabetic rats were randomly assigned into the IT group and the sham IT (SH) group. Bile acid profiles were measured using an ultra-performance liquid chromatography-tandem mass spectrometry. Glucose metabolism was monitored after oral administration of FXR inhibitor and agonist. And the expression of key FXR target genes were measured. Results: The levels of β-muricholic acid (P = 0.047), tauro-α-muricholic acid and tauro-β-muricholic acid (P < 0.001) in plasma in the IT group were higher than those in the SH group, and the levels of taurocholic acid (P = 0.049) and turoursodeoxycholic acid (P = 0.030) were lower than those in the SH group. After inhibition of intestinal FXR, the glucose metabolism in the SH group was improved. When FXR agonist was given, the blood glucose level was increased in both groups. After sacrifice, the levels of glycoursodeoxycholic acid, tauro-α-muricholic acid and tauro-β-muricholic acid in liver and ileum tissues were higher than those in the SH group (P < 0.05), the level of α- muricholic acid (P < 0.001) in liver tissues were lower than that in the SH group. Moreover, the expression of CYP7A1 mRNA (P < 0.001) and FGF15 mRNA (P = 0.001) in the IT group was significantly higher, and the expression of PEPCK mRNA (P = 0.004), SREPB1c mRNA (P = 0.005) and SRB1 mRNA (P = 0.001) were significantly lower than that in the SH group. Conclusions: We demonstrate a remarkable heterogeneity of BA profiles after IT, FXR activation might has a detrimental effect on glucose metabolism.

Keywords: bile acids and salts; diabetes mellitus; farnesoid X receptor; glucose; ileum.

Figure 1

the schematic diagram of ileum transposition and sham surgery. a, the schematic map of ileum transposition. The distal ileum was transposed into the proximate intestine, and the bile acids are mainly reabsorbed in ileum, so the enterohepatic circulation of bile acids could be accelerated. b, the sham surgery involved same incisions and transections at the jejunum and ileum to simulate the trauma of ileum transposition. IT, ileum transposition. SH, sham ileum transposition.

Figure 2

Maximum food intake curve and body weight curve of rats. a, Maximum food intake curve of two group rats. The maximum food intake in 24 hours of the IT group was less than that of the SH group after surgery (P < 0.001). b, Body weight curve of two group rats. From 12 weeks after surgery, the body weight of the IT group was less than that of the SH group (P < 0.001). IT, ileum transposition. SH, sham ileum transposition.

Figure 3

Glucose metabolism of two groups. a, Fasting glucose curve of the two groups. The lower fasting glucose level was observed in the IT group after surgery (P < 0.001). b, AUC_OGTT value during the postoperative period. The AUC_OGTT value of the IT group was less than that of the SH group after surgery (P < 0.001). c, Glucose curve during the OGTT before surgery. d, Glucose curve during the OGTT at postoperative week 4. e, Glucose curve during the OGTT at postoperative week 12. f, Glucose curve during the OGTT at postoperative week 20.

Figure 4

Bile acid profile changes after IT. a, Bile acid profiles in plasma after IT. The level of β-MCA, T-α-MCA and T-β-MCA in the IT group was higher than that in the SH group, and the level of TCA and TDCA was lower than that in the SH group (P < 0.05). b, Bile acid profiles in liver after IT. The level of GUDCA, T-α-MCA and T-β-MCA in liver tissues in the IT group was higher than that in the SH group, and the level of α-MCA was lower than that in the SH group (P < 0.05). c, Bile acid profiles in ileum after IT. The levels of GUDCA, T-α-MCA and T-β-MCA in the IT group were higher than those in the SH group (P < 0.05). α-MCA, α-muricholic acid. β-MCA, β-muricholic acid. CA, cholic acid. CDCA, chenodeoxycholic acid. DCA, deoxycholic acid. HDCA, hyodeoxycholic acid. LCA, lithocholic acid. GCA, glycocholic acid. GCDCA, glycochenodeoxycholic acid. GDCA, glycodeoxycholic acid. GUDCA, glycoursodeoxycholic acid. T-α-MCA, tauro-α-muricholic acid. T-β-MCA, tauro-β-muricholic acid. TCA, taurocholic acid. TDCA, turoursodeoxycholic acid. THDCA, taurohyodeoxycholic acid. TUDCA, tauroursodeoxycholic acid. IT, ileum transposition. SH, sham ileum transposition.

Figure 5

Blood glucose levels after FXR inhibition and activation. a, Glucose curve after oral FXR inhibitor administration. The glucose level and the AUC_OGTT value in the SH group rats decreased after FXR inhibition (P = 0.049). There was no significant difference in the glucose level and the AUC_OGTT value after FXR inhibition in the IT group (P = 0.081). b, Glucose curve after oral FXR agonist administration. The glucose level (P = 0.003) and the AUC_OGTT value (P = 0.011) in the IT group rats increased after FXR activation. The FPG level increased after FXR agonist administration (P = 0.013), and there was no significant difference in the AUC_OGTT value before and after FXR activation. FXR, farnesoid X receptor. IT, ileum transposition. SH, sham ileum transposition. IT', ileum transposition group rats after oral drug administration. SH', sham ileum transposition group rats after oral drug administration.

Figure 6

the expression of key FXR target genes. a, the expression of CYP7A1 mRNA in liver. The FXR activation could reduce the expression of CYP7A1. b, the expression of FGF15 mRNA in ileum. The FGF15 expression is inhibited by activated FXR. c, the expression of PEPCK mRNA in liver. Phosphoenolpyruvate carboxykinase is a key enzyme in the gluconeogenesis pathway d, the expression of SRB1 mRNA in ileum. Scavenger receptor class B type 1 is involved in cholesterol transportation. e, the expression of SREPB1c mRNA in liver. Sterol regulatory element binding proteins induction causes lipogenesis, hypertriglyceridemia and steatohepatitis. FXR, farnesoid X receptor. IT, ileum transposition. SH, sham ileum transposition.