Silencing of functional p53 attenuates NAFLD by promoting HMGB1-related autophagy induction
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ORIGINAL ARTICLE
Silencing of functional p53 attenuates NAFLD by promoting HMGB1‑related autophagy induction Xuequn Zhang1 · Yiming Lin1 · Sisi Lin2 · Chunxiao Li1 · Jianguo Gao1 · Zemin Feng1 · Jinghua Wang1 · Jie Zhang1 · Hong Zhang1 · Yuwei Zhang1 · Xueyang Chen1 · Shenghui Chen1 · Chengfu Xu1 · Youming Li1 · Chaohui Yu1 · Hang Zeng1 Received: 22 April 2020 / Accepted: 22 June 2020 © The Author(s) 2020
Abstract Background and aim Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, but its pathogenesis remains imprecisely understood and requires further clarification. Recently, the tumor suppressor p53 has received growing attention for its role in metabolic diseases. In this study, we performed in vivo and in vitro experiments to identify the contribution of p53–autophagy regulation to NAFLD. Methods Livers from wild-type and p53 knockout mice as well as p53-functional HepG2 cells and p53-dysfunctional Huh7 cells were examined for autophagy status and HMGB1 translocation. In vivo and in vitro NAFLD models were established, and steatosis was detected. In the cell models, autophagy status and steatosis were examined by p53 and/or HMGB1 silencing. Results First, the silencing of p53 could induce autophagy both in vivo and in vitro. In addition, p53 knockout attenuated high-fat diet-induced NAFLD in mice. Similarly, knockdown of p53 could alleviate palmitate-induced lipid accumulation in cell models. Furthermore, high mobility group box 1 (HMGB1) was proven to contribute to the effect of silencing p53 on alleviating NAFLD in vitro as an autophagy regulator. Conclusion The anti-NAFLD effect of functional p53 silencing is associated with the HMGB1-mediated induction of autophagy.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12072-020-10068-4) contains supplementary material, which is available to authorized users. * Chaohui Yu [email protected] * Hang Zeng [email protected] 1
Department of GastroenterologyFirst Affiliated HospitalSchool of Medicine, Zhejiang University, Hangzhou 310003, China
Department of Pharmacy, Zhejiang Provincial People’s Hospital, Hangzhou 310014, China
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Hepatology International
Graphic abstract
Keywords p53 · Nonalcoholic fatty liver disease · Autophagy · High mobility group box 1 · p62 · High-fat diet · Mice · HepG2 · Huh7 · Mouse primary hepatocytes Abbreviations NAFLD Nonalcoholic fatty liver disease PA Palmitate HMGB1 High mobility group box 1 HCC Hepatocellular carcinoma HFD High-fat diet AMPK AMP-activated protein kinase DRAM Damage-regulated autophagy modulator BCL1 Beclin-1 SCD Standard chow diet H&E Hematoxylin and eosin GTT Glucose tolerance test ITT Insulin tolerance test DEME Dulbecco’s modified Eagle medium FBS Fetal bovine serum PBS Palmitate GFP Green fluorescent protein CQ Chloroquine
Introduction Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease commonly encountered in clinical practice in Western countr
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