title: The impact of cortisol in steatotic and non-steatotic liver surgery.
abstract: The intent of this study was to examine the effects of regulating cortisol levels on damage and regeneration in livers with and without steatosis subjected to partial hepatectomy under ischaemia-reperfusion. Ultimately, we found that lean animals undergoing liver resection displayed no changes in cortisol, whereas cortisol levels in plasma, liver and adipose tissue were elevated in obese animals undergoing such surgery. Such elevations were attributed to enzymatic upregulation, ensuring cortisol production, and downregulation of enzymes controlling cortisol clearance. In the absence of steatosis, exogenous cortisol administration boosted circulating cortisol, while inducing clearance of hepatic cortisol, thus maintaining low cortisol levels and preventing related hepatocellular harm. In the presence of steatosis, cortisol administration was marked by a substantial rise in intrahepatic availability, thereby exacerbating tissue damage and regenerative failure. The injurious effects of cortisol were linked to high hepatic acethylcholine levels. Upon administering an α7 nicotinic acethylcholine receptor antagonist, no changes in terms of tissue damage or regenerative lapse were apparent in steatotic livers. However, exposure to an M3 muscarinic acetylcholine receptor antagonist protected livers against damage, enhancing parenchymal regeneration and survival rate. These outcomes for the first time provide new mechanistic insight into surgically altered steatotic livers, underscoring the compelling therapeutic potential of cortisol-acetylcholine-M3 muscarinic receptors.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Cornide-Petronio
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Bujaldon
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Mariana
authors.initials: M
authors.lastname: Mendes-Braz
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Cindy G
authors.initials: CG
authors.lastname: Avalos de León
authors.affiliation: Transplant Biomedicals S.L., Barcelona, Spain.
authors.forename: Mónica B
authors.initials: MB
authors.lastname: Jiménez-Castro
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Álvarez-Mercado
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS, CIBEREHD, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Gracia-Sancho
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Liver Unit, Hospital Clínic, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Rodés
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors.forename: Carmen
authors.identifier: 0000-0002-5767-0676
authors.initials: C
authors.lastname: Peralta
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D018679:Cholinergic Agonists / Q000378:metabolism / Q000494:pharmacology; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism / Q000601:surgery*; D006498:Hepatectomy / Q000379:methods*; D006854:Hydrocortisone / Q000032:analysis* / Q000097:blood / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D008115:Liver Regeneration / Q000187:drug effects; D009765:Obesity / Q000097:blood / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018679:Cholinergic Agonists; D000109:Acetylcholine; D006854:Hydrocortisone
keywords: Partial hepatectomy; acetylcholine; cortisol; ischaemia-reperfusion; liver; steatosis