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Silencing of functional p53 attenuates NAFLD by promoting HMGB1-related autophagy induction
Xuequn Zhang1, Yiming Lin1, Sisi Lin2
1Department of GastroenterologyFirst Affiliated HospitalSchool of Medicine, Zhejiang University, Hangzhou, 310003, China.
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.
Insights
Silencing the tumor suppressor p53 promotes autophagy, which helps alleviate nonalcoholic fatty liver disease (NAFLD) by regulating high mobility group box 1 (HMGB1). This finding offers new insights into NAFLD pathogenesis.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Biology
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a prevalent global liver condition with incompletely understood mechanisms.
- The tumor suppressor p53 is increasingly recognized for its involvement in metabolic disorders.
Purpose of the Study:
- To investigate the role of p53-autophagy regulation in the development and progression of NAFLD.
- To elucidate the specific mechanisms by which p53 influences NAFLD pathogenesis.
Main Methods:
- Examined autophagy and HMGB1 translocation in wild-type and p53 knockout mouse livers and in HepG2/Huh7 cells.
- Established in vivo and in vitro NAFLD models to assess steatosis.
- Utilized p53 and/or HMGB1 silencing in cell models to analyze autophagy and steatosis.
Main Results:
- p53 silencing induced autophagy in both in vivo and in vitro settings.
- p53 knockout attenuated diet-induced NAFLD in mice and palmitate-induced lipid accumulation in cell models.
- High mobility group box 1 (HMGB1) was identified as an autophagy regulator mediating the anti-NAFLD effects of p53 silencing.
Conclusions:
- The protective effects of p53 silencing against NAFLD are linked to HMGB1-mediated autophagy induction.
- Targeting the p53-autophagy-HMGB1 pathway may represent a therapeutic strategy for NAFLD.
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