Release of senescence marker protein-30 into extracellular vesicles and its association with ascorbic acid levels in acetaminophen-induced acute liver injury

抄録

Senescence marker protein-30 (SMP30) is a redox-responsive protein involved in the biosynthesis of ascorbic acid that has been established to have cytoprotective effects in rodents. Previously, we reported that SMP30 is released into extracellular vesicle (EV) fractions in osteogenic disorder Shionogi (ODS) model rats. In the present study, we examined changes in hepatic SMP30 expression patterns and EV-associated SMP30 levels in acetaminophen (APAP)-induced acute liver injury. APAP administration was found to significantly reduce hepatic SMP30 expression at the mRNA and protein levels, whereas we detected marked SMP30 elevations in EV fractions. In addition, APAP treatment was observed to induce oxidative stress–associated liver injury, as evidenced by hepatomegaly, a depletion of hepatic total glutathione, increases in malondialdehyde levels, and an elevated AST and ALT activities. Although we detected an approximate 1.45-fold increase in serum ascorbic acid levels and modest elevation in hepatic ascorbic acid levels, hepatic SMP30 expression was not restored. This indicates that regulation is independent of ascorbic acid availability. Furthermore, APAP markedly induced the phosphorylation of ERK1/2 and STAT3. Rather than a passive leakage from necrotic hepatocytes, the reciprocal reduction in hepatic SMP30 and increase in EV-associated SMP30 are considered to be indicative of a signaling-dependent selective release process. These findings provide the first evidence linking EV-associated SMP30 expression with the serum ascorbic acid levels in APAP-induced acute liver injury, and contribute new insights into redox-responsive protein trafficking under conditions of acute hepatic injury.