Trabajo presentado en el The international liver congress, celebrado en Londres (Inglaterra) del 22 al 26 de junio de 2022.[Background and aims]: Activation of oval cells has been related to hepatocyte injury during chronic liver diseases including nonalcoholic fatty liver disease (NAFLD). However, oval cells plasticity can be affected by the pathological environment. We previously found a protection against hepatocyte cell death by inhibiting protein tyrosine phosphatase 1B (PTP1B). Herein, we investigated the molecular and cellular processes involved in the lipotoxic susceptibility in oval cells expressing or not PTP1B.
[Method]: Palmitic acid (PA) induced apoptotic cell death in wild-type (Ptpn1+/+) oval cells in parallel to oxidative stress and impaired autophagy. This lipotoxic effect was attenuated in oval cells lacking Ptpn1 that showed up-regulated antioxidant defences, increased unfolded protein response (UPR) signaling, higher endoplasmic reticulum (ER) content and elevated stearoyl CoA desaturase (Scd1) expression and activity.
[Results]: These effects in Ptpn1−/− oval cells concurred with an active autophagy, higher mitochondrial efficiency and a molecular signature of starvation, favoring lipid droplet (LD) formation and dynamics. Autophagy blockade in Ptpn1−/− oval cells reduced Scd1 expression, mitochondrial fitness, LD formation and restored lipoapoptosis, an effect also recapitulated by Scd1 silencing. Importantly, oval cells with LDs were found in livers from Ptpn1−/− mice with NAFLD.
[Conclusion]: Ptpn1 deficiency restrained lipoapoptosis in oval cells through a metabolic rewiring towards a “starvation-like” fate, favoring autophagy, mitochondrial fitness and LD formation. Dynamic LD-lysosomal interations likely ensured lipid recycling and, overall, these adaptations protect against lipotoxicity. The identification of LDs in oval cells from Ptpn1−/− mice with NAFLD opens new therapeutic perspectives to ensure oval cells viability and plasticity under lipotoxic liver damage
