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Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis

Nature Metabolism volume 1, pages 147–157 (2019)Cite this article

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Abstract

Extracellular matrix (ECM) homeostasis is essential for normal tissue function, and its disruption by iatrogenic injury, trauma, or disease results in fibrosis. Skin ECM homeostasis is maintained by a complex process that involves an integration of cytokine and environmental mediators. However, it is unclear, in both normal and disease states, how these multifactorial processes converge to shift ECM homeostasis towards accumulation or degradation. Here we show a consistent downregulation in fatty acid oxidation (FAO) and upregulation of glycolysis in fibrotic skin and in normal skin with abundant ECM. Perturbation of glycolysis and FAO pathway enzymes reveals their reciprocal effects in ECM upregulation and downregulation, respectively. Increasing peroxisome proliferator-activated receptor (PPAR) signalling, an inducer of the FAO pathway, generates a catabolic fibroblast phenotype characterised by inhibition of ECM transcription and enhanced ECM internalization and lysosomal degradation. In contrast, suppression of glycolysis inhibits ECM gene transcription and protein levels, independently of an intact FAO pathway or PPAR signalling. Moreover, we show that CD36, a multifunctional fatty acid transporter, connects the metabolic state of fibroblasts with their capacity for ECM regulation, as internalization and degradation of collagen-1 is abrogated in fibroblasts lacking CD36. Finally, restoring FAO and upregulating CD36 reduces ECM accumulation in murine skin fibrosis. These findings indicate that metabolic perturbation of ECM homeostasis may have broad implications for therapies aimed at ECM regulation, such as fibrosis, regenerative medicine, and ageing.

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Fig. 1: ECM accumulation in normal and fibrotic skin corresponds to a shift in metabolism from FAO to glycolysis.
Fig. 2: Enhancing FAO induces a catabolic fibroblast that downregulates ECM transcription and enhances ECM degradation.
Fig. 3: CD36 is metabolically regulated in fibroblasts and crucial for collagen-1 degradation.
Fig. 4: Pharmacological and cellular therapy restores FAO in skin and reduces ECM accumulation.

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Data availability

Transcriptomic data can be found on the National Center for Biotechnology Information (NCBI) gene expression omnibus (GEO) using ID GSE98157 for murine RNA-seq data and GSE98159 for human HT-12 array data. Software parameters have been uploaded onto Github: https://github.com/bhklab/SkinFibrosis. The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This research was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Physicians Services Incorporated Foundation, the Harry Barbarian Research Grant, the Mariano Elia Chair in Head and Neck Cancer Research, the Campbell Family Institute for Cancer Research, the Ministry of Health and Long-Term Care, and the Princess Margaret Cancer Centre Head and Neck Translational Program, with philanthropic funding from the Wharton family and Joe’s Team.

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Authors and Affiliations

  1. Department of Otolaryngology—Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada

    Xiao Zhao, David Goldstein, Ralph Gilbert & Ian Witterick

  2. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Xiao Zhao, Laleh Soltan Ghoraie, Kenneth Yip, Justin Williams, Scott V. Bratman, Laurie Ailles, Benjamin Haibe-Kains & Fei-Fei Liu

  3. Insitute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

    Xiao Zhao & Benjamin Haibe-Kains

  4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Pamela Psarianos, Hilary Pang, Ali Hussain, Ju Hee Lee, Scott V. Bratman, Laurie Ailles & Fei-Fei Liu

  5. Department of Otolaryngology—Head and Neck Surgery and Surgical Oncology, University Health Network, University of Toronto, Toronto, Ontario, Canada

    David Goldstein, Ralph Gilbert & Ian Witterick

  6. Department of Otolaryngology—Head and Neck Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada

    Ian Witterick

  7. Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Scott V. Bratman & Fei-Fei Liu

  8. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

    Scott V. Bratman & Fei-Fei Liu

  9. Department of Computer Science, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Benjamin Haibe-Kains

  10. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    Benjamin Haibe-Kains

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Contributions

X.Z., L.S.G., K.Y., D.G., R.G., I.W., S.V.B., L.A., B.H.-K., and F.-F.L. participated in the research design. X.Z, P.P., .H.P., A.H., J.H.L., and J.W. conducted experiments. X.Z., L.S.G., L.A., B.H.-K. contributed new reagents or analytic tools. G.Z., L.S.G., P.P., H.P., A.H., J.H.L. and J.W. performed data analysis. X.Z., L.S.G., P.P., K.Y., D.G., R.G., S.V.B., L.A., B.H.-K., and F.-F.L. wrote or contributed to the writing of the manuscript.

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Correspondence to Xiao Zhao or Fei-Fei Liu.

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Supplementary information

Supplementary Information

Supplementary Figures 1–35 and Supplementary Tables 1 and 2

Reporting Summary

Supplementary Dataset 1

qRT–PCR primers

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Zhao, X., Psarianos, P., Ghoraie, L.S. et al. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nat Metab 1, 147–157 (2019). https://doi.org/10.1038/s42255-018-0008-5

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