title: Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells.
abstract: OBJECTIVE
  Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine - which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH).
  
  
  METHODS
  hHSC were isolated from healthy human livers and nAChR expression analyzed - RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-α2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-β1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH).
  
  
  RESULTS
  hHSCs express muscle type (α1, β1, delta and epsilon) and neuronal type (α3, α6, α7, β2 and β4) nAChR subunits at the mRNA level. Among these subunits, α3, α7, β1 and ε were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p<0.05). Additionally, collagen1-α2 and TGF-β1 mRNA expression were significantly upregulated by nicotine and inhibited by mecamylamine. α1 and α3-nAChR mRNA expression was significantly upregulated in NASH fibrosis compared to normal livers.
  
  
  CONCLUSIONS
  Nicotine at levels in smokers' blood is pro-fibrogenic, through actions on hHSCs expressed nAChRs. Therefore, CS, via its nicotine content, may worsen liver fibrosis. Moreover, nicotinic receptor antagonists may have utility as novel anti-fibrotic agents.
authors: University College London, Centre for Hepatology, Royal Free Hospital, London, United Kingdom.
authors: Junpei
authors: J
authors: Soeda
authors: Maelle
authors: M
authors: Morgan
authors: Chad
authors: C
authors: McKee
authors: Angelina
authors: A
authors: Mouralidarane
authors: Chingi
authors: C
authors: Lin
authors: Tania
authors: T
authors: Roskams
authors: Jude A
authors: JA
authors: Oben
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000009:adverse effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D012907:Smoking / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D053773:Transforming Growth Factor beta1; D008464:Mecamylamine; D009538:Nicotine; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C