Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 27239-27251 |
| Number of pages | 13 |
| Journal | Journal of Biological Chemistry |
| Volume | 291 |
| Issue number | 53 |
| DOIs | |
| State | Published - Dec 30 2016 |
Funding
This work was supported, in whole or in part, by National Institutes of Health Grants R01 ES015024 and R21 ES025644 (to G. M. M.), K01 AR066579 (to R. B. H.), R56 HL127395 (to N. O. D.), and F32 HL134288 (to D. Wu) and American Heart Association Grant 15POST255900003 (to R. N.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology