Nrf2 Participates in Regulating Maternal Hepatic Adaptations to Pregnancy

Abstract

SummaryPregnancy induces widespread adaptive responses in maternal organ systems including the liver. The maternal liver exhibits significant growth by increasing the number and size of hepatocytes, by largely unknown mechanisms. Nrf2 mediates cellular defense against oxidative stress and inflammation and also regulates liver regeneration. To determine whether Nrf2 is involved in the regulation of maternal hepatic adaptations to pregnancy, we assessed the proliferation and size of maternal hepatocytes and the associated molecular events in wild-type and Nrf2-null mice at various stages of gestation. We found that wild-type maternal hepatocytes underwent proliferation and size reduction during the first half, and size increase without overt replication during the second half, of pregnancy. Although pregnancy decreased Nrf2 activity in the maternal liver, Nrf2 deficiency caused a delay in maternal hepatocyte proliferation, concomitant with dysregulation of the activation of Cyclin D1, E1, and, more significantly, A2. Remarkably, as a result of Nrf2 absence, the maternal hepatocytes were largely prevented from reducing their sizes during the first half of pregnancy, which was associated with an increase in mTOR activation. During the second half of pregnancy, maternal hepatocytes of both genotypes showed continuous volume increase accompanied by persistent activation of mTOR. However, the lack of Nrf2 resulted in dysregulation of the activation of the mTOR upstream regulator AKT1 and the mTOR target p70SK6 and thus disruption of the AKT1/mTOR/p70S6K pathway, which is known to control cell size. This suggests an mTOR-dependent and AKT1-and p70S6K-independent compensatory mechanism when Nrf2 is deficient. In summary, our study demonstrates that Nrf2 is required for normal maternal hepatic adjustments to pregnancy by ensuring proper regulation of the number and size of maternal hepatocytes.

Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration

“…Mechanistically, we revealed that Nrf2 is indispensable for the proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration. As reported in our previous publication, the absence of Nrf2 leads to increased levels of cyclin A2 mRNA and protein in the maternal liver exhibiting hepatocyte proliferation during gestation, which demonstrates that Nrf2 is a cyclin A2 transcriptional suppressor (37). In this study, we found that Nrf2 deficiency results in elevated cyclin A2 mRNA and protein expression in the regenerating liver.…”

Telocytes in Pregnancy-Induced Physiological Liver Growth

“…In the present study, we demonstrated two peaks of hepatocytes proliferation occurring at early stages and late stages of pregnancy as shown by EdU and Albumin double immunostaining. The increased proliferation of hepatocytes related to pregnancy has previously been documented [13,14,67,69], while the occurrence of two proliferative peaks of hepatocytes during pregnancy in the present study was firstly reported here. We hypothesized that the possible reasons may be related to different species (rat vs. mouse) [13], ages (old vs. young) [14], and animal models (pregnancy vs. ovariectomy or pseudopregnancy) [14,67] applied in our study and in others.…”

“…To date, the mechanisms underlying hepatic adaptions to pregnancy are largely unknown [10,11,13,14,[67][68][69]. In the present study, we demonstrated two peaks of hepatocytes proliferation occurring at early stages and late stages of pregnancy as shown by EdU and Albumin double immunostaining.…”

NRF2, not always friendly but perhaps misunderstood

“…In mice with genetic deletion of NRF2, a high‐fat diet progresses to nonalcoholic steatohepatitis, in contrast to a simple fatty change seen in the wild‐type mice . The cellular and gene expression adaptations of liver to pregnancy are also dependent on NRF2, with disruption of the AKT1/mTOR pathway seen in NRF2‐null mice …”