Protective role of biliverdin against bile acid-induced oxidative stress in liver cells

摘要

The accumulation of bile acids affects mitochondria causing oxidative stress. Antioxidant defense is accepted to include biotransformation of biliverdin (BV) into bilirubin (BR) through BV reductase alpha (BVR alpha). The mutation (c.214C > A) in BLVRA results in a non-functional enzyme (mutBVR alpha). Consequently, homozygous carriers suffering from cholestasis develop green jaundice. Whether BVR alpha deficiency reduces BV-dependent protection against bile acids is a relevant question because a screening of the mut-BLVRA allele (a) in 311 individuals in Greenland revealed that this SNP was relatively frequent in the Inuit population studied (1% a/a and 4.5% Lambda/a). In three human liver cell lines an inverse correlation between BVR alpha expression (HepG2 > Alexander > HuH-7) and basal reactive oxygen species (ROS) levels was found, however the ability of BV to reduce oxidative stress and cell death induced by deoxycholic acid (DCA) or potassium dichromate (PDC) was similar in these cells. The transduction of BVR alpha or mutBVR alpha in human placenta JAr cells with negligible BVR alpha expression or the silencing of endogenous BVR alpha expression in liver cells had no effect on DCA-induced oxidative stress and cell death or BV-mediated cytoprotection. DCA stimulated both superoxide anion and hydrogen peroxide production, whereas BV only inhibited the latter. DCA and other dihydroxy-bile acids, but not PDC, induced up-regulation of both BVR alpha and heme oxygenase-1 (HO-1) in liver cells through a FXR independent and BV insensitive mechanism. In conclusion, BV exerts direct and BVR alpha-independent antioxidant and cytoprotective effects, whereas bile acid accumulation in cholestasis stimulates the expression of enzymes favoring the heme biotransformation into BV and BR. (C) 2016 Elsevier B.V. All rights reserved.