title: Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion.
abstract: During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH+I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH+I/R.
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ben Mosbah
authors.forename: I
authors.initials: I
authors.lastname: Alfany-Fernández
authors.forename: C
authors.initials: C
authors.lastname: Martel
authors.forename: M A
authors.initials: MA
authors.lastname: Zaouali
authors.forename: M
authors.initials: M
authors.lastname: Bintanel-Morcillo
authors.forename: A
authors.initials: A
authors.lastname: Rimola
authors.forename: J
authors.initials: J
authors.lastname: Rodés
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.forename: J
authors.initials: J
authors.lastname: Roselló-Catafau
authors.forename: C
authors.initials: C
authors.lastname: Peralta
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D053454:Caspase 12 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000601:surgery*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006360:Heat-Shock Proteins / Q000378:metabolism; D006498:Hepatectomy; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D056811:Unfolded Protein Response; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051702:Activating Transcription Factor 6; D053454:Caspase 12; D045304:Cytochromes c; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006360:Heat-Shock Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D010654:Phenylbutyrates; D013655:Taurochenodeoxycholic Acid; D050994:Voltage-Dependent Anion Channels; C497113:Atf6 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; C000605508:Gsk3b protein, rat