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HIF-1α–PPARγ–mTORC1 signaling pathway-mediated autophagy induces inflammatory response in pancreatic cells in rats with hyperlipidemic acute pancreatitis

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Abstract

Objective

The incidence of hyperlipidemic acute pancreatitis (HLAP) has rapidly increased in recent years in China. Autophagy has been implicated in the inflammatory response of pancreatic cells in HLAP, but the molecular mechanisms remain unclear.

Methods

In this study, the role of HIF-1α–PPARγ–mTORC1 pathway-mediated autophagy in the inflammatory response of pancreatic cells and the underlying molecular mechanism were investigated in a rat model of HLAP using immunohistochemistry, ELISA, electron microscopy, and western blot analysis.

Results

The results revealed that autophagy was significantly increased and pancreatic injury was exacerbated in HLAP rats, and the inflammatory response was further exacerbated by treatment with rapamycin but relieved by treatment with 3-MA. Hyperlipidemia induced upregulation of HIF-1α and downregulation of PPARγ, which in turn led to an increase in autophagy and consequently exacerbation of the inflammatory response of pancreatic cells.

Conclusions

HIF-1α–PPARγ–mTORC1 pathway-mediated autophagy plays a critical role in the inflammatory response of pancreatic cells in HLAP, and interference with the HIF-1α–PPARγ–mTOR pathway can serve as a new strategy for the prevention and treatment of HLAP.

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Data availability

The dataset supporting the conclusions of this article are included within the article.

Abbreviations

HLAP:

Hyperlipidemic acute pancreatitis

HIF-1α:

Hypoxia-inducible factor 1-alpha

mTORC1:

Mammalian Target of Rapamycin Complex 1

PPARγ:

Peroxisome proliferator-activated receptor-γ

Beclin-1:

Myosin-like BCL-2 interacting protein

LC3-II:

Microtubule-associated protein light chain 3-II

siRNA:

Small Interfering Ribonucleic Acid

3-MA:

3-methyladenine

TG:

Triglyceride

TC:

Total cholesterol

AMY:

Amylase

LPS:

Lipase

TNF-α:

Tumor necrosis factor-α

PI3K:

Phosphatidylinositol 3-kinase

Akt:

Protein kinase B

ROS:

Reactive oxygen species

ATG:

Autophagy related gene

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Acknowledgements

We thank National Natural Sciences Foundation of China ,Innovative and Entrepreneurial Doctor Program of Jiangsu Provincial, Top Talents Support Program for young and middle-aged people of Wuxi Health committee and The Scientific Research Project of Wuxi Health committee for their fnancial support.We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by the National Natural Science Foundations of China (No. 81760334), Innovative and Entrepreneurial Doctor Program of Jiangsu Provincial, Top Talents Support Program for young and middle-aged people of Wuxi Health committee and The Scientific Research Project of Wuxi Health committee (Youth Project, No.Q201912).

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Author notes

    Authors and Affiliations

    1. Medical College of Soochow University, Suzhou, 215123, Jiangsu, China

      Yumei Ma

    2. Digestive Department of Qinghai Provincial People’s Hospital, Xining, 810007, China

      Yumei Ma, Xiaolin Li, Zhilan Liu, Xiaohong Xue & Yingcai Ma

    3. Wuxi Huishan District People’s Hospital, Wuxi, 214187, Jiangsu, China

      Yaping Wang

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    Contributions

    MYM and LXL contributed to the conception and design of the study, acquired the majority of the data, and drafted the manuscript.LZL contributed to the conception and design of the study and acquired some of the data. XXH contributed to the design of the study and interpretation of the data.WYP and MYC contributed to the design of the study, and interpretation of data, and substantively revised the manuscript. All the authors reviewed and approved the final draft of the manuscript.

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    Correspondence to Yaping Wang.

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    Ethical approval and consent to participate

    This study was conducted in accordance with the guidelines of the Declaration of Helsinki. All animal experimental protocols applied in this study were conducted in accordance with the standards of the Animal Ethics Committee of Huishan District People’s Hospital of Wuxi City, China.

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    The authors declare no competing interests.

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    Yumei Ma and Xiaolin Li contributed equally to this work.

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    Ma, Y., Li, X., Liu, Z. et al. HIF-1α–PPARγ–mTORC1 signaling pathway-mediated autophagy induces inflammatory response in pancreatic cells in rats with hyperlipidemic acute pancreatitis. Mol Biol Rep 50, 8497–8507 (2023). https://doi.org/10.1007/s11033-023-08639-3

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