Enhanced Hepatic Nrf2 Activation After Ursodeoxycholic Acid Treatment in Patients with Primary Biliary Cirrhosis

Abstract

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.

Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

“…Our data are in agreement with the observation that CDCA treatment activated Nrf2 and induced its target genes in the liver and intestinal cells (Tan et al, 2007). Ursodeoxycholic acid, another bile acid, has been used in clinical studies to treat liver diseases including primary biliary cirrhosis, and a large part of its beneficial aspect may be attributable to its property of Nrf2 activation (Okada et al, 2008;Kawata et al, 2010). Hence, it is presumed that an enhanceosome complex containing C/EBP␤ and Nrf2 may work together in inducing target genes by CDCA.…”

Does Hepatic Oxidative Stress Enhance Activation of Nuclear Factor-E2-Related Factor in Patients with Nonalcoholic Steatohepatitis?

“…The protein concentration of samples in the SDS sample buffer was determined by using Peterson's modification of the micro-Lowry method. Western blot analysis following SDS-PAGE was performed using specific antibodies as described previously (3). The following primary antibodies were used: rabbit polyclonal anti-Nrf 2 (1:200 dilution), rabbit polyclonal anti-HO-1 (Stressgen, Victoria, BC, Canada; 1:5000 dilution), rabbit polyclonal anti-cGCS (Lab Vision Corp., Fremont, CA; 1:400 dilution), goat polyclonal anti-GPx2 (Abcam; 1:200 dilution), mouse monoclonal anti-TRX antibody (Redox Bio Science, Inc., Kyoto, Japan; 1:100 dilution), mouse monoclonal anti-TrxR1 (Santa Cruz Biotechnology, Santa Cruz, CA; 1:100 dilution), and anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Trevigen, Gaithersburg, MD; 1:1000 dilution) antibodies.…”

Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice

“…Ursodeoxycholic acid (UDCA), the only drug approved by the FDA specifically for the treatment of primary biliary cirrhosis (PBC), has both direct and indirect antioxidant properties [5]. It acts directly by scavenging hydroxyl radicals and indirectly through the induction of endogenous antioxidant defenses, including increasing the expression of -glutamylcysteine synthetase regulatory subunit and increasing the rate of glutathione (GSH) synthesis.…”

“…It acts directly by scavenging hydroxyl radicals and indirectly through the induction of endogenous antioxidant defenses, including increasing the expression of -glutamylcysteine synthetase regulatory subunit and increasing the rate of glutathione (GSH) synthesis. Recently, a novel therapeutic mechanism of UDCA action via Nrf2 activation has been suggested and may represent another drug target in cholestatic liver diseases [5, 6]. Nonetheless, the effectiveness of UDCA is limited to the early stages of PBC [7].…”