Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-?1/Smad2/3 signalling.

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 TNF?/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-?1. 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 ?-smooth muscle actin (?-SMA), ?1-collagen, vimentin and TGF-?1 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 TNF?/CHX and in LX2 cells exposed to conditioned medium. UDCA-LPE also decreased phosphorylated Smad3 and Smad2 directly induced by TGF-?1. Inhibition of TGF-?1/Smad2/3 signalling with down-regulation of target genes was confirmed in HHStec. In vivo, UDCA-LPE decreased hepatic ?-SMA, ?1-collagen and TGF-?1 expression and markedly lowered ?-SMA protein and collagen deposition in MCD mice.

Conclusions and implications

By blocking TGF-?1/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.

SUBMITTER: Pathil A 

PROVIDER: S-EPMC4253459 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature