Both authors contributed equally to this work.
Metabolic and Steatohepatitis
Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX
Article first published online: 12 AUG 2013
© 2013 The Authors. Liver International published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Volume 33, Issue 10, pages 1566–1574, November 2013
How to Cite
Liver Int. 2013; 33: 1566–1574
- Issue published online: 6 OCT 2013
- Article first published online: 12 AUG 2013
- Accepted manuscript online: 16 JUN 2013 05:53AM EST
- Manuscript Accepted: 28 MAY 2013
- Manuscript Revised: 23 MAY 2013
- Manuscript Received: 20 DEC 2012
- National Natural Science Foundation of China. Grant Numbers: 81071843, 81272266, 30910103915
- Basic-Clinical Collaborative Research Fund
- CCMU. Grant Number: 12JL-L05
- Beijing Institute of Hepatology. Grant Number: BJIH-01201
- damage-regulated autophagy modulator;
- non-alcoholic fatty liver disease
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.
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.
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.
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.