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The cytoprotective mechanisms of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) have not been fully clarified. UDCA has some antioxidant properties. Nuclear factor-E2-related factor-2 (Nrf2) plays a critical role in protecting a variety of tissues against oxidative stress. Therefore, to investigate the potential antioxidant effects of UDCA in PBC, we determined the intracellular status of both oxidant stress and antioxidant defenses in paired pre- and posttreatment liver biopsies from 13 PBC patients by immunodetection of 8-hydroxydeoxyguanosine (8-OHdG), Nrf2-, and Nrf2-mediated antioxidant proteins. After UDCA treatment, the number of 8-OHdG-positive hepatocytes or bile duct cells decreased with improvement of hepatic injury. The hepatic levels of both total and phosphorylated Nrf2 protein were increased, along with upregulation of nuclear phosphorylated Nrf2 expression in bile duct cells. In addition, the levels of both thioredoxin (TRX) and thioredoxin reductase 1 (TrxR1) protein were increased in the liver after UDCA. The upregulation of hepatic TRX or TrxR1 protein expression positively correlated with that of total Nrf2 protein expression. In conclusion, UDCA treatment can enhance hepatic Nrf2 activation and upregulate hepatic TRX and TrxR1 protein expression. Hepatic Nrf2 activation may play a role in the therapeutic response to UDCA in PBC.

The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.

Background/AimsChanges in lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antiviral therapy have been reported in recent years. However, the clinical aspects of disturbed lipid metabolism in chronic HCV infection have not been fully elucidated.MethodsDynamic changes in serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and apolipoprotein levels in patients infected with HCV genotype 1b were examined during combination therapy with daclatasvir (DCV) and asunaprevir (ASV).ResultsTotal, LDL−, and HDL-cholesterol levels increased rapidly and persistently after week 4. Apolipoprotein (apo) A-I, apo B, apo C-II, and apo C-III levels were significantly higher at week 4 than at week 0. In contrast, apo A-II and apo E levels were significantly lower. The differences in LDL− and HDL-cholesterol levels were positively correlated with those of apo B and apo A-I, respectively. Interestingly, in patients with non-sustained virological response, these cholesterol levels decreased rapidly after viral breakthrough or viral relapse. Furthermore, similar changes were observed for apo A-I, apo B and apo C-III levels.ConclusionsClearance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism.

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