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The upregulation of Annexin A2 by TLR4 pathway facilitates lipid accumulation and liver injury via blocking AMPK/mTOR-mediated autophagy flux during the development of non-alcoholic fatty liver disease

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Abstract

Background and aims

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. In this study, we aimed to investigate the role and regulatory mechanism of Annexin A2 (ANXA2) in the pathogenesis of NAFLD.

Methods

Histological analyses and ELISA were used to illuminate the expression of ANXA2 in NAFLD and healthy subjects. The role of ANXA2 was evaluated using high-fat diet (HFD)-fed mice via vein injection of adeno-associated viruses (AAV) knocking down ANXA2 or non-targeting control (NC) shRNAs. Moreover, HepG2 and LO2 cells were employed as in vitro hepatocyte models to investigate the expression and function of ANXA2.

Results

ANXA2 was confirmed to be one of three hub genes in liver injury, and its expression was positively correlated with NAFLD activity score (NAS) and macrophage infiltration in NAFLD. Moreover, ANXA2 was significantly upregulated in NAFLD patients and HFD-fed mice. LPS/TLR4 pathway strongly upregulated ANXA2 expression, which is mediated by direct ANXA2 promoter binding by TLR4 downstream NF-κB p65 and c-Jun transcription factors. Increased ANXA2 expression was correlated with decreased autophagy flux and autophagy was activated by the depletion of ANXA2 in the models of NAFLD. Furthermore, ANXA2 interference led to the activation of AMPK/mTOR signaling axis, which may play a causal role in autophagy flux and the amelioration of steatosis.

Conclusions

ANXA2 is a pathological predictor and promising therapeutic target for NAFLD. ANXA2 plays a crucial role in linking inflammation to hepatic metabolic disorder and injury, mainly through the blockage of AMPK/mTOR-mediated lipophagy.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82070624, No. 82272624, No. 81401985, No. 31801113 and No. 82273206), China Postdoctoral Science Foundation (No. 2018M632830, No. 2020M670039ZX and No. 2021M701793), Key Project of Health Commission of Jiangsu Province (No. ZDB2020006), Natural Science Foundation of Jiangsu Province (No. BK20211105), Social Development Foundation of Nantong City (No. MS12021073, No. MS22022005, No. JCZ21061 and No. MS22022014), Science and technology project of Nantong City (No. MS22022109 and No. JC12022026), Jiangsu Provincial Research Hospital (No. YJXYY202204).

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Author notes

  1. Haifeng Wu, Meng Zhou and Qin Jin have contributed equally to this work as Joint First Authors.

Authors and Affiliations

  1. Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Xisi Road, Nantong, 226001, China

    Haifeng Wu, Meng Zhou, Xun Wang, Yue Xu, Ming Li, Shuhui Chen, Hongpei Wu, Mingbing Xiao, Lishuai Qu & Jinxia Liu

  2. Department of Emergency Medicine, Affiliated Nantong Hospital of Shanghai University, The Sixth People’s Hospital of Nantong), Nantong, Jiangsu, China

    Haifeng Wu

  3. Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China

    Qin Jin

  4. College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, China

    Qin Tang

  5. College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China

    Qi Wang

  6. Department of Immunology, Medical School of Nantong University, Nantong, Jiangsu, China

    Baoying Hu

  7. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Xisi Road, Nantong, 226001, China

    Qiong Zhang

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  1. Haifeng Wu
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Contributions

Conceptualization, Methodology and Project administration: JL, QZ. Investigation: MZ. Formal analysis: MZ, HW, JQ. Resources: XW, HW. Data Curation: YX, ML, SC, QT, QW. Writing-Original Draft: MZ, HW. Validation: LQ, QZ, CL, MX. Writing-Review & Editing: JL, LQ, QZ, BH. Visualization: MZ, HW, JQ. Funding acquisition: JL.

Corresponding authors

Correspondence to Lishuai Qu, Qiong Zhang or Jinxia Liu.

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Conflict of interest

The authors declare that they do not have any conflicts of interest.

Ethics approval

The human study was approved by the Human Research Ethics Committee of the Affiliated Hospital of Nantong University and conducted in accordance with all relevant ethical regulations. All animal use and viral protocols were approved by the Committee on the Use of Live Animals in Teaching and Research, Nantong University.

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Written consent was obtained from all the participants involved in this study.

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Wu, H., Zhou, M., Jin, Q. et al. The upregulation of Annexin A2 by TLR4 pathway facilitates lipid accumulation and liver injury via blocking AMPK/mTOR-mediated autophagy flux during the development of non-alcoholic fatty liver disease. Hepatol Int (2024). https://doi.org/10.1007/s12072-023-10622-w

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