title: Sympathetic nervous system catecholamines and neuropeptide Y neurotransmitters are upregulated in human NAFLD and modulate the fibrogenic function of hepatic stellate cells.
abstract: BACKGROUND
  Sympathetic nervous system (SNS) signalling regulates murine hepatic fibrogenesis through effects on hepatic stellate cells (HSC), and obesity-related hypertension with SNS activation accelerates progression of non-alcoholic fatty liver disease (NAFLD), the commonest cause of chronic liver disease. NAFLD may lead to cirrhosis. The effects of the SNS neurotransmitters norepinephrine (NE), epinephrine (EPI) and neuropeptide Y (NPY) on human primary HSC (hHSC) function and in NAFLD pathogenesis are poorly understood.
  
  
  OBJECTIVE
  to determine the mechanistic effects of NE/EPI/NPY on phenotypic changes in cultured hHSC, and to study SNS signalling in human NAFLD livers.
  
  
  METHODS
  Freshly isolated hHSC were assessed for expression of cathecholamine/neuropeptide Y receptors and for the synthesis of NE/EPI. The effects of NE/EPI/NPY and adrenoceptor antagonists prazosin (PRZ)/propranolol (PRL) on hHSC fibrogenic functions and the involved kinases and interleukin pathways were examined. Human livers with proven NAFLD were then assessed for upregulation of SNS signalling components.
  
  
  RESULTS
  Activated hHSC express functional α/β-adrenoceptors and NPY receptors, which are upregulated in the livers of patients with cirrhotic NAFLD. hHSC in culture synthesize and release NE/EPI, required for their optimal basal growth and survival. Exogenous NE/EPI and NPY dose-dependently induced hHSC proliferation, mediated via p38 MAP, PI3K and MEK signalling. NE and EPI but not NPY increased expression of collagen-1α2 via TGF-β without involvement of the pro-fibrogenic cytokines leptin, IL-4 and IL-13 or the anti-fibrotic cytokine IL-10.
  
  
  CONCLUSIONS
  hHSC synthesize and require cathecholamines for optimal survival and fibrogenic functionality. Activated hHSC express directly fibrogenic α/β-adrenoceptors and NPY receptors, upregulated in human cirrhotic NAFLD. Adrenoceptor and NPY antagonists may be novel anti-fibrotic agents in human NAFLD.
authors.affiliation: Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sigala
authors.forename: Chad
authors.initials: C
authors.lastname: McKee
authors.forename: Junpei
authors.initials: J
authors.lastname: Soeda
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.forename: Maelle
authors.initials: M
authors.lastname: Morgan
authors.forename: Ching-I
authors.initials: CI
authors.lastname: Lin
authors.forename: Clare
authors.initials: C
authors.lastname: Selden
authors.forename: Sara
authors.initials: S
authors.lastname: Vander Borght
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.forename: Jude A
authors.initials: JA
authors.lastname: Oben
mesh_terms: D001483:Base Sequence; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000378:metabolism; D017931:DNA Primers; D005234:Fatty Liver / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D009638:Norepinephrine / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002395:Catecholamines; D017931:DNA Primers; D007378:Interleukins; D009478:Neuropeptide Y; D011941:Receptors, Adrenergic; D016212:Transforming Growth Factor beta; D003094:Collagen; D009638:Norepinephrine
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