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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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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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.
The authors declare no competing interests.
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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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