title: 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.
authors: Fleur
authors: F
authors: Lien
authors: Alexandre
authors: A
authors: Berthier
authors: Emmanuel
authors: E
authors: Bouchaert
authors: Céline
authors: C
authors: Gheeraert
authors: Jeremy
authors: J
authors: Alexandre
authors: Geoffrey
authors: G
authors: Porez
authors: Janne
authors: J
authors: Prawitt
authors: Hélène
authors: H
authors: Dehondt
authors: Maheul
authors: M
authors: Ploton
authors: Sophie
authors: S
authors: Colin
authors: Anthony
authors: A
authors: Lucas
authors: Alexandre
authors: A
authors: Patrice
authors: François
authors: F
authors: Pattou
authors: Hélène
authors: H
authors: Diemer
authors: Alain
authors: A
authors: Van Dorsselaer
authors: Christophe
authors: C
authors: Rachez
authors: Jelena
authors: J
authors: Kamilic
authors: Albert K
authors: AK
authors: Groen
authors: Bart
authors: B
authors: Staels
authors: Philippe
authors: P
authors: Lefebvre
mesh_terms: D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000595:Amino Acid Sequence; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D001692:Biological Transport; D018938:Caco-2 Cells; D002780:Cholestasis, Intrahepatic / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000263:Adenylate Kinase; D000620:Aminoimidazole Carboxamide; D001647:Bile Acids and Salts; D007004:Hypoglycemic Agents; D008687:Metformin; D018160:Receptors, Cytoplasmic and Nuclear; D012265:Ribonucleotides; D015534:Trans-Activators; D000099150:Receptor, Farnesoid X-Activated; C031143:AICA ribonucleotide