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Omentin-1 induces mechanically activated fibroblasts lipogenic differentiation through pkm2/yap/pparγ pathway to promote lung fibrosis resolution

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis.

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Data and materials availability

RNA-seq and microarray data reanalyzed in the paper are in publicly available libraries from GEO under accession nos. GSE135893. All data associated with this study are present in the paper or the Supplementary Materials.

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Acknowledgements

Not applicable.

Funding

National Natural Science Foundation of China 82070068 (LZQ), National Natural Science Foundation of China 81870059 (LZQ), National Natural Science Foundation of China 82200085 (ZY), Natural Science Foundation of Changsha kq2202116 (ZY), and Central South University 2022ZZTS0837 (ZYN).

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Authors and Affiliations

  1. Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China

    Yunna Zhang, Jiafeng Fu, Yanfen Chang, Yujia Qiu, Min Shao, Yang Han, Dandan Feng, Ziqiang Luo & Yan Zhou

  2. Department of Physiology, Changzhi Medical College, Changzhi, 046000, China

    Chen Li

  3. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410013, China

    Xiaohong Li & Haipeng Cheng

  4. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410013, China

    Shaojie Yue

  5. Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, China

    Ziqiang Luo

  6. Center for Immunology and Inflammatory Diseases, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Zhengwang Sun

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  1. Yunna Zhang
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  2. Jiafeng Fu
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  14. Yan Zhou
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Contributions

Conceptualization: ZYN, ZY, LZQ; Data curation: ZYN, ZY; Formal analysis: ZYN, ZY, LC; Investigation: ZYN, FJF, CYF, LXH, CHP; Project administration: LZQ, ZY, ZYN; Resources: LZQ, ZY, HY, FDD; Software: QYJ, SM; Supervision: LZQ, ZY, YSJ, ZWS; Validation: LZQ, ZY; Writing—original draft: ZYN, ZY and Writing—review & editing: ZYN, ZWS, ZY, LZQ.

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Correspondence to Ziqiang Luo or Yan Zhou.

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The animal study protocol was approved by the ethics committee of the Central South University Science Research Center (Changsha, China) (protocol code: 2020sydw0715).

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Zhang, Y., Fu, J., Li, C. et al. Omentin-1 induces mechanically activated fibroblasts lipogenic differentiation through pkm2/yap/pparγ pathway to promote lung fibrosis resolution. Cell. Mol. Life Sci. 80, 308 (2023). https://doi.org/10.1007/s00018-023-04961-y

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