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S100A4 promotes inflammation but suppresses lipid accumulation via the STAT3 pathway in chronic ethanol-induced fatty liver

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Abstract

S100A4, a member of the S100 calcium-binding protein family, has been identified in a subpopulation of liver macrophages and promotes liver fibrosis via hepatic stellate cell activation. However, the specific role of S100A4 in alcoholic liver disease (ALD) has not been well investigated. Here, S100A4 knockout (S100A4−/−) mice were used in a chronic-binge ethanol model for studying the role of S100A4 and its related molecular mechanism in ALD. S100A4 expression was increased in ethanol-induced liver tissues of wild-type (WT) mice. Macrophage-derived S100A4 promoted liver inflammation but suppressed lipid accumulation under the ethanol feeding condition. S100A4 deficiency promoted ethanol-induced liver injury and hepatic fat accumulation. Further mechanistic studies found that S100A4 inhibited liver fat accumulation mainly by activating the STAT3 pathway and downregulating lipogenic gene expression, especially that of SREBP-1c. In AML-12 cells, a STAT3 inhibitor abolished STAT3 levels and decreased the expression of SREBP1c. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly promoted ethanol-induced liver injury and fatty accumulation. Thus, S100A4 may represent a potential candidate target for the prevention and treatment of ethanol-induced fatty liver. In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.

Key messages

In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.

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Abbreviations

ALD:

Alcoholic liver disease

WT:

Wild type

AFL:

Alcoholic fatty liver

ACC1:

Acetyl-CoA carboxylase 1

FAS:

Fatty acid synthase

SCD1:

Stearoyl-coenzyme A desaturase 1

SREBP:

Sterol regulatory element-binding protein

ChREBP:

Carbohydrate-response element-binding protein

IFN-γ:

Interferon-γ

IL:

Interleukin

TNF-α:

Tumor necrosis factor-α

MIP-2:

Macrophage inflammatory protein 2

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

GRO-α:

Growth-regulated oncogene-α

MCP-1:

Monocyte chemoattractant protein-1

ALT:

Alanine transaminase

AST:

Aspartate aminotransferase

Cho:

Cholesterol

TG:

Triglyceride

EMT:

Epithelial-mesenchymal transition

Ly6G:

Lymphocyte antigen 6 complex locus G6D

MPO:

Myeloperoxidase

CYP2E1:

Cytochromep450-2E1

SOD:

Superoxide dismutase1

CAT:

Catalase

TGF-β:

Transforming growth factor β

Col1α1:

Type I collagen alpha-1

TIMP-1:

The tissue inhibitor of metalloproteinases-1

MMP-9:

Matrix metalloproteinase-9

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Funding

This work was financially supported by the National Natural Science Foundation of China (81772497and 81370543) and the Natural Science Foundation of Beijing (7162116).

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Authors and Affiliations

  1. The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People’s Republic of China

    Qi Yuan, Shasha Hou, Tian Tian, Jinsheng He, Zhinan Chen & Jinhua Zhang

  2. The Chinese Academy of Inspection and Quarantine, Beijing, People’s Republic of China

    Junfeng Zhai

  3. The State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, People’s Republic of China

    Yingjie Wu & Zhenlong Wu

  4. The Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer, Fourth Military Medical University, Xi’an, People’s Republic of China

    Zhinan Chen

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  1. Qi Yuan
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Contributions

Q.Y., Z.C., and J.Z. participated in the study design. Q.Y., S.H., J.Z., and Y.W. collected the data. Q.Y., Z.W., J.H., and J.Z. analyzed and interpreted the data. J.Z., Q.Y., and T.T. wrote the manuscript.

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Correspondence to Jinhua Zhang.

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Yuan, Q., Hou, S., Zhai, J. et al. S100A4 promotes inflammation but suppresses lipid accumulation via the STAT3 pathway in chronic ethanol-induced fatty liver. J Mol Med 97, 1399–1412 (2019). https://doi.org/10.1007/s00109-019-01808-7

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  • DOI: https://doi.org/10.1007/s00109-019-01808-7

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