title: Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX.
abstract: OBJECTIVE
  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 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.
  
  
  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.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Jinli
authors.initials: J
authors.lastname: Lou
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Jiming
authors.initials: J
authors.lastname: Yin
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Anna
authors.initials: A
authors.lastname: Wang
authors.forename: Daojie
authors.initials: D
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D019301:Oleic Acid / Q000009:adverse effects; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; C512709:DRAM1 protein, human; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019301:Oleic Acid