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Background & Aims  Apoptosis 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.    Methods  HepG2 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.    Results   OA  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 si RNA  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.    Conclusions  p53 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.

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