Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM‐induced autophagy or BAX

Abstract

Background & AimsApoptosis mediated by p53 plays a pathological role in the progression of hepatosteatosis. It is noteworthy that p53 can promote the expression of damage-regulated autophagy modulator (DRAM), an inducer of autophagy-mediated apoptosis. However, the relationship between p53-mediated apoptosis and autophagy in hepatosteatosis remains elusive. This study aimed to examine how p53 orchestrates autophagy and apoptosis to affect hepatosteatosis.MethodsHepG2 cells were treated with oleic acid (OA) for 24 h to induce hepatosteatosis. Mice were fed a high-fat diet for 20 or 40 weeks to induce hepatosteatosis.ResultsOA induced a dose-dependent increase in steatosis severity and apoptosis. OA also induced autophagy, which was a critical inducer of apoptosis in mild steatosis induced by 400 μM OA, but not in the more severe steatosis induced by 800 and 1200 μM OA. p53 inhibition by siRNA mostly blocked OA-induced apoptosis and autophagy. Moreover, OA-induced autophagy was DRAM-dependent and primarily occurred in the mitochondria (mitophagy), where DRAM was localized. In severe steatosis induced by 1200 μM OA, apoptosis was mainly dependent on p53-induced expression of BAX, which was also localized to the mitochondria. Our in vivo study showed that p53 expression increased in both mild and severe hepatosteatosis. Increased DRAM expression and autophagy were identified in mild hepatosteatosis, whereas greater BAX expression was observed in severe hepatosteatosis.Conclusionsp53 may induce apoptosis via different mechanisms. DRAM-mediated mitophagy is a primary apoptotic inducer in mild hepatosteatosis, whereas p53-induced BAX expression mainly induces apoptosis in severe hepatosteatosis.

Blueberry, combined with probiotics, alleviates non-alcoholic fatty liver diseaseviaIL-22-mediated JAK1/STAT3/BAX signaling

“…30 Moreover, Liu et al found that the increased BAX level accelerates apoptotic death in severe fatty degeneration. 31 Similarly, our results showed that BAX was down-regulated in the NAFLD group. Furthermore, the IL-22 siRNA increased the expression of BAX, both in NAFLD cells and in a rat model under BP treatment.…”

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

“…DRAM is an inducer of autophagy-mediated apoptosis, and localization of DRAM in the mitochondria leads to autophagy (41). As an effector of p53-mediated apoptosis, DRAM is a p53 target gene inducing macroautophagy (34).…”

Autophagy and apoptosis in liver injury

“…[34][35][36] Interestingly, DRAM/mitophagy signaling mediates apoptosis only in mild hepatosteatosis, whereas p53/BAX pathway induces apoptosis mainly in severe hepatosteatosis. 37 TNFa can induce autophagy in trophoblasts leading to the activation of apoptosis-intrinsic pathway. Knockdown of Atg5 prevents TNFa-dependent activation of proapoptotic caspases.…”