科研之友
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摘要
Background and PurposeChronic 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 ApproachTo 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-LPEin vivo, C57BL/6 mice were fed a MCD diet for 11 weeks followed by 30mg<bold>kg(</bold>-1) UDCA-LPE 3x per week for 2.5 weeks. Key ResultsExpression 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 ImplicationsBy 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.
- 出版日期2014-11
