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

Authors

  • Kai Liu,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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    • Both authors contributed equally to this work.
  • Jinli Lou,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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    • Both authors contributed equally to this work.
  • Tao Wen,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Jiming Yin,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Bin Xu,

    1. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Wei Ding,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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  • Anna Wang,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Daojie Liu,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Chao Zhang,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Dexi Chen,

    1. Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
    2. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
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  • Ning Li

    Corresponding author
    1. Division of HCC Research, Beijing Institute of Hepatology, Beijing, China
    • Infectious Disease Medical Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Correspondence

Ning Li, MD., Beijing You'an Hospital, Capital Medical University

8 Xi Tou Tiao, You An Men Wai, Feng Tai, 100069 Beijing, China

Tel: +86 10 6329 2337

Fax: +86 10 6305 7109

e-mail: liningya@ccmu.edu.cn

Abstract

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 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.

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