Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signalling

• Verfasst von: Pathil-Warth, Anita [VerfasserIn]
• Verfasst von: Müller, Jan [VerfasserIn]
• Verfasst von: Ludwig, Johannes Maximilian [VerfasserIn]
• Verfasst von: Wang, Jiliang [VerfasserIn]
• Verfasst von: Warth, Arne [VerfasserIn]
• Verfasst von: Chamulitrat, Walee [VerfasserIn]
• Verfasst von: Stremmel, Wolfgang [VerfasserIn]
• Titel: Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signalling
• Verf.angabe: Anita Pathil, Jan Mueller, Johannes M. Ludwig, Jiliang Wang, Arne Warth, Walee Chamulitrat and Wolfgang Stremmel
• E-Jahr: 2014
• Jahr: September 5, 2014
• Umfang: 14 S.
• Fussnoten: Gesehen am 18.12.2020
• Titel Quelle: Enthalten in: British journal of pharmacology
• Ort Quelle: Malden, MA : Wiley, 1946
• Jahr Quelle: 2014
• Band/Heft Quelle: 171(2014), 22, Seite 5113-5126
• ISSN Quelle: 1476-5381
• DOI: doi:10.1111/bph.12837
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Actins
• Sach-SW: Animals
• Sach-SW: Anti-Inflammatory Agents
• Sach-SW: Cell Line
• Sach-SW: Collagen Type I
• Sach-SW: Gene Expression Regulation
• Sach-SW: Hepatic Stellate Cells
• Sach-SW: Humans
• Sach-SW: Liver Cirrhosis
• Sach-SW: Lysophospholipids
• Sach-SW: Male
• Sach-SW: Mice, Inbred C57BL
• Sach-SW: Signal Transduction
• Sach-SW: Smad2 Protein
• Sach-SW: Smad3 Protein
• Sach-SW: Transforming Growth Factor beta1
• Sach-SW: Ursodeoxycholic Acid
• Sach-SW: Vimentin
• K10plus-PPN: 174319479X

Abstract

BACKGROUND AND PURPOSE: 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. - EXPERIMENTAL APPROACH: 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. - KEY 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 AND IMPLICATIONS: 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.