title: Propranolol, a β-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis.
abstract: Prazosin an α1-adrenoceptor (AR) antagonist has been shown to reduce liver injury in a mouse model of non-alcoholic steatohepatitis (NASH) and is suggested as a potential treatment of NASH especially given its concomitant anti-fibrotic properties. The effect however, of β-AR blockade in non-cirrhotic NASH is unknown and is as such investigated here. In the presence of the β-blocker propranolol (PRL), mice fed normal chow or a half methionine and choline deficient diet, supplemented with ethionine (HMCDE), to induce NASH, showed significantly enhanced liver injury, as evidenced by higher hepatic necrosis scores and elevated serum aminotransferases (ALT). Mechanistically, we showed that murine hepatocytes express α and β adrenoceptors; that PRL directly induces hepatocyte injury and death as evidenced by increased release of lactate dehydrogenase, FASL and TNF-α from hepatocytes in the presence of PRL; and that PRL activated the apoptotic pathway in primary hepatocyte cultures, as indicated by upregulation of Fas receptor and caspase-8 proteins. The β-AR antagonist PRL therefore appears to enhance liver injury through induction of hepatocyte death via the death pathway. Further studies are now required to extrapolate these findings to humans but meanwhile, β-AR antagonists should be avoided or used with caution in patients with non-cirrhotic NASH as they may worsen liver injury.
authors.affiliation: Institute for Liver and Digestive Health, University College London, United Kingdom.
authors.forename: Chad
authors.initials: C
authors.lastname: McKee
authors.forename: Junpei
authors.initials: J
authors.lastname: Soeda
authors.forename: Esra
authors.initials: E
authors.lastname: Asilmaz
authors.forename: Barbara
authors.initials: B
authors.lastname: Sigalla
authors.forename: Maelle
authors.initials: M
authors.lastname: Morgan
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sinelli
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Jude A
authors.initials: JA
authors.lastname: Oben
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002794:Choline / Q000494:pharmacology; D003470:Culture Media / Q000494:pharmacology; D004195:Disease Models, Animal; D005001:Ethionine / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000293:injuries* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D011433:Propranolol / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D003470:Culture Media; D053222:Fas Ligand Protein; D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; D011433:Propranolol; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D002794:Choline; D005001:Ethionine
keywords: Apoptosis; HPC; Hepatocytes; NAFLD; NASH; Non-alcoholic fatty liver disease; OC; PRL; PRZ; Propranolol; Sympathetic nervous system; hepatic progenitor cell; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; oval cell; prazosin; propranolol