title: Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signalling.
abstract: OBJECTIVE
  Chronic hepatic inflammation results in liver fibrosis. As effective anti-fibrogenic agents are lacking, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate with anti-inflammatory and anti-apoptotic properties for tis effects on hepatic fibrogenesis.
  
  
  METHODS
  To stimulate fibrogenesis, LX2 hepatic stellate cells were cultured with conditioned medium from CL48 liver cells after exposure to stress-inducing conditions - methionine-choline-deficient (MCD) medium or TNFα/cycloheximide (CHX) - with or without UDCA-LPE preincubation. Anti-fibrogenic effects of UDCA-LPE were further studied in CL48 and LX2 cells and in primary human hepatic stellate cells (HHStec) directly exposed to TGF-β1. To test UDCA-LPE in vivo, C57BL/6 mice were fed a MCD diet for 11 weeks followed by 30 mg·kg(-1) UDCA-LPE 3× per week for 2.5 weeks.
  
  
  RESULTS
  Expression of α-smooth muscle actin (α-SMA), α1-collagen, vimentin and TGF-β1 was down-regulated by up to 93% by UDCA-LPE in LX-2 cells cultured with conditioned medium. Also, UDCA-LPE inhibited Smad3 phosphorylation in CL48 cells incubated with MCD medium or TNFα/CHX and in LX2 cells exposed to conditioned medium. UDCA-LPE also decreased phosphorylated Smad3 and Smad2 directly induced by TGF-β1. Inhibition of TGF-β1/Smad2/3 signalling with down-regulation of target genes was confirmed in HHStec. In vivo, UDCA-LPE decreased hepatic α-SMA, α1-collagen and TGF-β1 expression and markedly lowered α-SMA protein and collagen deposition in MCD mice.
  
  
  CONCLUSIONS
  By blocking TGF-β1/Smad2/3 signalling, UDCA-LPE suppressed key mediators of hepatic fibrogenesis. Thus, UDCA-LPE could be suitable for prevention of fibrotic progression of chronic liver disease.
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Pathil
authors.forename: Jan
authors.initials: J
authors.lastname: Mueller
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Ludwig
authors.forename: Jiliang
authors.initials: J
authors.lastname: Wang
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014746:Vimentin / Q000235:genetics
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D008246:Lysophospholipids; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C000598975:ursodeoxycholyl lysophosphatidylethanolamide; D014580:Ursodeoxycholic Acid