title: Farnesoid X receptor activation promotes cell proliferation via PDK4-controlled metabolic reprogramming.
abstract: Farnesoid X receptor (FXR) plays a pivotal role in the regulation of various metabolic pathways as well as liver regeneration. However, the casual link between cell proliferative effects during liver regeneration and metabolic regulation of FXR was elusive. In this study, we found that FXR activation significantly promotes HepG2 cell proliferation accompanied with metabolic switch towards the excessive accumulation of aerobic glycolytic intermediates including lactic acid, pyruvate and the subsequently increased biosynthesis of glycine. This FXR-induced metabolic switch was found dependent on an up-regulation of pyruvate dehydrogenate kinase 4 (PDK4), a FXR target gene. FXR agonists were found to promote liver regeneration in the murine model of APAP induced liver injury, which was associated with a metabolic switch favoring the accumulation of glycolytic intermediates as precursors for generation of biomass. However, FXR activation has little effect on the glycolytic metabolism in healthy primary hepatocytes in vitro and the liver of healthy mice in vivo. Therefore, we conclude that FXR may promote the proliferation of tumor cells and the hepatocytes in the process of liver regeneration by activating the PDK4-mediated metabolic reprogramming to generate glycolytic intermediates essential for rapid biomass generation, establishing a mechanistic link between cell proliferation and metabolic switch.
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.|Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mengqiu
authors.initials: M
authors.lastname: Wu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008115:Liver Regeneration; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007555:Isoxazoles; D011494:Protein Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C403287:pyruvate dehydrogenase kinase 4; C412815:GW 4064