ursodoxicoltaurine and Liver-Cirrhosis

No direct comparison of tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) has yet been carried out in the treatment of liver cirrhosis in China. We designed a double-blind randomized trial to evaluate the potential therapeutic efficacy of TUDCA in liver cirrhosis, using UDCA as parallel control. The enrolled 23 patients with liver cirrhosis were randomly divided into TUDCA group (n=12) and UDCA group (n=11), and given TUDCA and UDCA respectively at the daily dose of 750 mg, in a randomly assigned sequence for a 6-month period. Clinical, biochemical and histological features, and liver ultrasonographic findings were evaluated before and after the study. According to the inclusion criteria, 18 patients were included in the final analysis, including 9 cases in both two groups. Serum ALT, AST and ALP levels in TUDCA group and AST levels in UDCA group were significantly reduced as compared with baseline (P<0.05). Serum albumin levels were significantly increased in both TUDCA and UDCA groups (P<0.05). Serum markers for liver fibrosis were slightly decreased with the difference being not significant in either group. Only one patient in TUDCA group had significantly histological relief. Both treatments were well tolerated and no patient complained of side effects. It is suggested that TUDCA therapy is safe and appears to be more effective than UDCA in the treatment of liver cirrhosis, particularly in the improvement of the biochemical expression. However, both drugs exert no effect on the serum markers for liver fibrosis during 6-month treatment.

Topics: Adult; Cholagogues and Choleretics; Double-Blind Method; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Taurochenodeoxycholic Acid; Treatment Outcome; Ursodeoxycholic Acid

Geniposide (GE), the active compound derived from Gardeniae Fructus, possesses valuable bioactivity for liver diseases, but GE effects on bile duct ligation (BDL)-induced cholestasis remain unclear. This study aimed to elucidate the influence of GE on BDL-induced liver fibrosis and to investigate the underlying mechanisms.. GE (25 or 50 mg/kg) were intragastrical administered to C57BL/6 J mice for two weeks to characterize the hepatoprotective effect of GE on BDL-induced liver fibrosis. NLRP3 inflammasome activation was detected in vivo, and BMDMs were isolated to explore whether GE directly inhibited NLRP3 inflammasome activation. Serum bile acid (BA) profiles were assessed utilizing UPLC-MS/MS, and the involvement of SIRT1/FXR pathways was identified to elucidate the role of SIRT1/FXR in the hepaprotective effect of GE. The veritable impact of SIRT1/FXR signaling was further confirmed by administering the SIRT1 inhibitor EX527 (10 mg/kg) to BDL mice treated with GE.. GE treatment protected mice from BDL-induced liver fibrosis, with NLRP3 inflammasome inhibition. However, development in vitro experiments revealed that GE could not directly inhibit NLRP3 activation under ATP, monosodium urate, and nigericin stimulation. Further mechanistic data showed that GE activated SIRT1, which subsequently deacetylated FXR and restored CDCA, TUDCA, and TCDCA levels, thereby contributing to the observed hepaprotective effect of GE. Notably, EX527 treatment diminished the hepaprotective effect of GE on BDL-induced liver fibrosis.. This study first proved the hepaprotective effect of GE on liver fibrosis in BDL mice, which was closely associated with the restoration of BA homeostasis and NLRP3 inflammasome inhibition. The activation of SIRT1 and the subsequent FXR deacetylation restored the BA profiles, especially CDCA, TUDCA, and TCDCA contents, which was the main contributor to NLRP3 inhibition and the hepaprotective effect of GE. Overall, our work provides novel insights that GE as well as Gardeniae Fructus might be the potential attractive candidate for ameliorating BDL-induced liver fibrosis.

Topics: Animals; Bile Acids and Salts; Bile Ducts; Chromatography, Liquid; Fibrosis; Inflammasomes; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Sirtuin 1; Tandem Mass Spectrometry

The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death.

Topics: Animals; Apoptosis; Biliary Tract; Biliary Tract Diseases; Blotting, Western; Caspase 12; Caspase 3; Cholagogues and Choleretics; Cholestasis; Disease Models, Animal; Fibrosis; Gene Expression; Liver; Liver Cirrhosis; Male; Mice; Reverse Transcriptase Polymerase Chain Reaction; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Tumor Necrosis Factor-alpha; Unfolded Protein Response

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of nonalcoholic steatohepatitis. The ER stress response is activated in the livers of mice fed a methionine- and choline-deficient (MCD) diet, yet the role of ER stress in the pathogenesis of MCD diet-induced steatohepatitis is unknown. Using chemical chaperones on hepatic steatosis and markers of inflammation and fibrosis in mice fed a MCD diet, we aim to determine the effects of reducing ER stress. C57BL/6J mice were fed a MCD diet with or without the ER chemical chaperones 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) for 2 wk. TUDCA and PBA effectively attenuated the ER stress response in MCD diet-fed mice, as evidenced by reduced protein levels of phosphorylated eukaryotic initiation factor 2α and phosphorylated JNK and suppression of mRNA levels of CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78 kDa, and X-box binding protein 1. However, PBA and TUDCA did not decrease MCD diet-induced hepatic steatosis. MCD diet-induced hepatic inflammation, as evidenced by increased plasma alanine aminotransferase and induction of hepatic TNFα expression, was also not reduced by PBA or TUDCA. PBA and TUDCA did not attenuate MCD diet-induced upregulation of the fibrosis-associated genes tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9. ER chemical chaperones reduce MCD diet-induced ER stress, yet they do not improve MCD diet-induced hepatic steatosis, inflammation, or activation of genes associated with fibrosis. These data suggest that although the ER stress response is activated by the MCD diet, it does not have a primary role in the pathogenesis of MCD diet-induced steatohepatitis.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Cholesterol; Choline Deficiency; Diet; Endoplasmic Reticulum; Fatty Liver; Gene Expression; Inflammation; Liver; Liver Cirrhosis; Male; Methionine; Mice; Mice, Inbred C57BL; Molecular Chaperones; Phenylbutyrates; Real-Time Polymerase Chain Reaction; Stress, Physiological; Taurochenodeoxycholic Acid

The pathogenesis of hepatic fibrosis in cholestasis is still unknown, except for endotoxaemia. There is a possibility that the elevation of serum bile acids in cholestasis may play an important role in hepatic fibrogenesis due to a reaction to perisinusoidal cells, such as Ito or Kupffer cells. To assess the effects of bile acids, we investigated the cell proliferation and collagen formation of primary cultured Ito cells that were incubated with a Kupffer cell conditioned medium (KCCM) treated with either taurochenodeoxycholic acid (TCDCA) or tauroursodeoxycholic acid (TUDCA) in short-term (8 h) or long-term (48 h) cultures. KCCM treated with TCDCA (100 mumol/L) but not with TUDCA increased cell proliferation of Ito cells in short-term cultures and also partially elevated collagen formation by Ito cells in long-term cultures. The release of tumour necrosis factor-alpha (TNF alpha) from Kupffer cells was increased by TCDCA in short-term cultures, but not in long-term cultures. The release of transforming growth factor-beta 1 (TGF beta 1) from Kupffer cells was increased by TCDCA in long-term cultures, but not in the short-term cultures. TUDCA showed no significant effect on the release of TNF alpha and TGF beta 1 from Kupffer cells. TUDCA or TCDCA itself showed no direct effect on the cell proliferation and collagen formation of Ito cells. In conclusion, these findings are thus considered to show the potentially important role of TCDCA on the development of hepatic fibrosis in the early phase of cholestasis without endotoxaemia.

Topics: Animals; Cell Division; Cells, Cultured; Collagen; Culture Media, Conditioned; Kupffer Cells; Liver; Liver Cirrhosis; Male; Rats; Rats, Wistar; Taurochenodeoxycholic Acid; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha