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

Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signalling / Anita Pathil, Jan Mueller, Johannes M. Ludwig, Jiliang Wang, Arne Warth, Walee Chamulitrat and Wolfgang Stremmel

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..

Medienart:	E-Artikel

Erscheinungsjahr:	September 5, 2014 2014
Erschienen:	September 5, 2014

Enthalten in:	Zur Gesamtaufnahme - volume:171
Enthalten in:	British journal of pharmacology - 171(2014), 22, Seite 5113-5126

Sprache:	Englisch

Beteiligte Personen:	Pathil-Warth, Anita, 1981- [VerfasserIn] Müller, Jan [VerfasserIn] Ludwig, Johannes Maximilian, 1984- [VerfasserIn] Wang, Jiliang [VerfasserIn] Warth, Arne, 1979- [VerfasserIn] Chamulitrat, Walee, 1959- [VerfasserIn] Stremmel, Wolfgang, 1952- [VerfasserIn]

Links:	Volltext [lizenzpflichtig]

Themen:	Actins Animals Anti-Inflammatory Agents Cell Line Collagen Type I Gene Expression Regulation Hepatic Stellate Cells Humans Liver Cirrhosis Lysophospholipids Male Mice, Inbred C57BL Signal Transduction Smad2 Protein Smad3 Protein Transforming Growth Factor beta1 Ursodeoxycholic Acid Vimentin

Anmerkungen:	Gesehen am 18.12.2020

Umfang:	14

doi:	10.1111/bph.12837

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	174319479X

Internformat


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650		4	\|a Actins
650		4	\|a Animals
650		4	\|a Anti-Inflammatory Agents
650		4	\|a Cell Line
650		4	\|a Collagen Type I
650		4	\|a Gene Expression Regulation
650		4	\|a Hepatic Stellate Cells
650		4	\|a Humans
650		4	\|a Liver Cirrhosis
650		4	\|a Lysophospholipids
650		4	\|a Male
650		4	\|a Mice, Inbred C57BL
650		4	\|a Signal Transduction
650		4	\|a Smad2 Protein
650		4	\|a Smad3 Protein
650		4	\|a Transforming Growth Factor beta1
650		4	\|a Ursodeoxycholic Acid
650		4	\|a Vimentin
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Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signalling / Anita Pathil, Jan Mueller, Johannes M. Ludwig, Jiliang Wang, Arne Warth, Walee Chamulitrat and Wolfgang Stremmel

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