TY - JOUR
T1 - Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk
AU - Lien, Fleur
AU - Berthier, Alexandre
AU - Bouchaert, Emmanuel
AU - Gheeraert, Céline
AU - Alexandre, Jeremy
AU - Porez, Geoffrey
AU - Prawitt, Janne
AU - Dehondt, Hélène
AU - Ploton, Maheul
AU - Colin, Sophie
AU - Lucas, Anthony
AU - Patrice, Alexandre
AU - Pattou, François
AU - Diemer, Hélène
AU - van Dorsselaer, Alain
AU - Rachez, Christophe
AU - Kamilic, Jelena
AU - Groen, Albert K.
AU - Staels, Bart
AU - Lefebvre, Philippe
PY - 2014
Y1 - 2014
N2 - 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 e 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
AB - 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 e 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
U2 - https://doi.org/10.1172/JCI68815
DO - https://doi.org/10.1172/JCI68815
M3 - Article
C2 - 24531544
SN - 0021-9738
VL - 124
SP - 1037
EP - 1051
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 3
ER -