Oxidative stress and localization status of hepatocellular transporters: Impact on bile secretion and role of signaling pathways

BASIGLIO CL; CROCENZI FA; SANCHEZ POZZI EJ; ROMA MG

ANTIOXIDANTS & REDOX SIGNALING

MARY ANN LIEBERT INC

Lugar: New York; Año: 2021

1523-0864

Significance: Most hepatopathies are primarily or secondarily cholestatic in nature. Oxidative stressis a common feature among them, and induces alterations in the machinery to produce bile bytriggering endocytic internalization of hepatocellular transporters, thus causing cholestasis. This iscritical, since it leads to accelerated transporter degradation, which could explain the commonposttranscriptional downregulation of transporter expression in human cholestatic diseases.Recent Advances: The mechanisms involved in oxidative stress-induced hepatocellular transporterinternalization are being revealed. F-actin cytoskeleton disorganization and/or detachment of crosslinkingactin proteins that afford transporter stability have been characterized as causal factors.Activation of redox-sensitive signaling pathways leading to changes in phosphorylation status ofthese structures is involved, including Ca2+-mediated activation of classical and novel PKC isoformsor redox-signaling cascades downstream of NADPH oxidase.Critical Issues: Despite the well-known occurrence of hepatocellular transporter internalization inhuman hepatopathies, the cholestatic implications of this phenomenon have been overlooked.Accordingly, no specific treatment has been established in the clinical practice for itsprevention/reversion.Future Directions: We need to improve our knowledge on the pro-oxidant triggering factors and themultiple signaling pathways that mediate this oxidative injury in each cholestatic hepatopathy, so asto envisage tailor-made therapeutic strategies for each case. Meanwhile, administration ofantioxidants or heme oxygenase-1 induction to elevate the hepatocellular levels of the endogenousscavenger bilirubin are promising alternatives that need to be re-evaluated and implemented. Theymay complement current treatments in cholestasis aimed to transcriptionally improve transporterexpression, by affording membrane stability to the de novo synthesized transporters.