Transforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production
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TGF-β promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. Here, we report that TGF-β induces expression of glycolytic genes and increases glycolytic flux. TGF-β also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.
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Monocytes and macrophages are capable of remarkable functional plasticity, displaying diverse phenotypes during wound healing dependent on multiple cues including the environmental niche and the temporal stage of tissue injury and repair.
“Furthermore, monocytes and macrophages are capable of remarkable functional plasticity, displaying diverse phenotypes during wound healing dependent on multiple cues including the environmental niche61,62 and the temporal stage of tissue injury and repair63–66.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [66]
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- Authors
- Nigdelioglu, R., Hamanaka, R. B., Meliton, A. Y., O'Leary, E., Witt, L. J., Cho, T., Sun, K., Bonham, C., Wu, D., Woods, P. S., Husain, A. N., Wolfgeher, D., Dulin, N. O., Chandel, N. S., & Mutlu, G. M.
- Affiliations
- University of Chicago (US)
- Northwestern University (US)
- Corresponding author
- Mutlu, Gökhan M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 291
- Issue
- 53
- Pages
- 27239-27251
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5207151
- OpenAlex
- W2565062778
- Cited by
- 169
- References
- 31
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 26 · 2023: 18 · 2022: 10 · 2021: 27 · 2020: 14 · 2019: 12 · 2018: 6 · 2017: 6
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01 ES015024, R21 ES025644)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01 AR066579)
- National Institutes of Health (R56 HL127395, F32 HL134288)
- American Heart Association (15POST255900003)
- National Heart, Lung, and Blood Institute (T32 HL007605)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- TGF-beta, collagen synthesis, serine biosynthesis, de novo serine synthesis, glycine metabolism, idiopathic pulmonary fibrosis, pulmonary fibrosis, PHGDH, SHMT2, glycolysis, fibroblast metabolism, metabolic reprogramming, therapeutic target
- MeSH terms
- Cells, Cultured, Collagen, Fibroblasts, Gene Expression Regulation, Glycolysis, Humans, Lung, Serine, Glycine Hydroxymethyltransferase, Transforming Growth Factor beta, Phosphoglycerate Dehydrogenase, Idiopathic Pulmonary Fibrosis
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