Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk

Abstract

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis.

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

“…However, after metformin treatment, TBAs and TC were both significantly reduced, suggesting that the secretion and excretion of BAs are promoted. A possible explanation for these results is that metformin interacts with and inhibits FXR thus increasing Cyp7a1 and bile acid transporters (Besp and Mrp2) [22]. Thus, our results suggest that administration of metformin in DM rat may increase bile flow favoring cholestasis.…”

“…Besides, a former study showed that FXR was important in mediating the increase of FGF21 [3]. While another study showed that metformin activated AMPK can phosphorylate and inhibit FXR as well as its target proteins [22]. We hypothesized that there may exist other mechanisms in mediating metformin and FGF21 actions which is independent of FXR.…”

“…Recent finding suggested that metformin could also interact with mammalian target of rapamycin complex 1 (mTORC1) signaling as well as pancreatic and duodenal homeobox 1 (PDX1) thus affecting pancreatic functions [21]. Besides, metformin has been shown to affect Farnesoid X Receptor (FXR) activities through AMPK-FXR crosstalk [22]. However, several studies on the effects of metformin on FXR activity are controversial.…”

“…However, several studies on the effects of metformin on FXR activity are controversial. On one hand, metformin has been shown to phosphorylate FXR and inhibit its target genes [22]. On the other hand, several studies suggested that metformin could induce FXR target gene such as FGF21 expression in an AMPKdependent pathway [23,24].…”

“…As regards FGF19, it has already been suggested that FGF19 is produced by the activation of FXR, the bile acid nuclear receptor; and Fleur Lien et al suggested that FXR was mediated by metformin through AMPK-FXR crosstalk [22]. The mechanistic explanation for the reduced FGF19 in DM+METF rats may be that metformin inhibits FXR transcription thus inhibiting FGF19 production [22]. There are several mechanisms responsible for the increased FGF21 by metformin treatment.…”