title: Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human.
abstract: OBJECTIVE
  The purpose of this study was to determine whether 3'-5'-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2-4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear factor-E2 related-factor 2 (NRF2) is a transcription factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed.
  
  
  RESULTS
  Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1-dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, which was decreased by the PKA inhibitor, H-89. Moreover, fasting induced NRF2 target gene expression was decreased in liver and hepatocytes of SIRT1 liver-specific null mice and NRF2-null mice. Lastly, NRF2 and SIRT1 were recruited to MAREs and Antioxidant Response Elements (AREs) in the human ABCC2 promoter.
  
  
  METHODS
  Oxidative stress mediated NRF2 activation is well described, yet the influence of basic metabolic processes on NRF2 activation is just emerging.
  
  
  CONCLUSIONS
  The current data point toward a novel role of nutrient status in regulation of NRF2 activity and the antioxidant response, and indicates that cAMP/PKA and SIRT1 are upstream regulators for fasting-induced activation of the NRF2-ARE pathway.
authors.affiliation: 1 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island , Kingston, Rhode Island.
authors.forename: Supriya R
authors.initials: SR
authors.lastname: Kulkarni
authors.forename: Ajay C
authors.initials: AC
authors.lastname: Donepudi
authors.forename: Jialin
authors.initials: J
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Qiuqiong C
authors.initials: QC
authors.lastname: Cheng
authors.forename: Maureen V
authors.initials: MV
authors.lastname: Driscoll
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Angela L
authors.initials: AL
authors.lastname: Slitt
mesh_terms: D024506:5' Flanking Region; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D061745:Antioxidant Response Elements; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005215:Fasting / Q000502:physiology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015124:8-Bromo Cyclic Adenosine Monophosphate; D018528:ATP-Binding Cassette Transporters; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D051267:NF-E2-Related Factor 2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1; D014157:Transcription Factors; C000715087:ABCC2 protein, human; C486497:PPARGC1A protein, human; C114462:multidrug resistance-associated protein 3