TGF-beta 1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts
Web of Science
AuthorSmith, ER; Hewitson, TD
Source TitleScientific Reports
AffiliationMedicine and Radiology
Document TypeJournal Article
CitationsSmith, E. R. & Hewitson, T. D. (2020). TGF-beta 1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts. SCIENTIFIC REPORTS, 10 (1), https://doi.org/10.1038/s41598-020-74919-8.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578649
TGF-β1 reprograms metabolism in renal fibroblasts, inducing a switch from oxidative phosphorylation to aerobic glycolysis. However, molecular events underpinning this are unknown. Here we identify that TGF-β1 downregulates acetyl-CoA biosynthesis via regulation of the pyruvate dehydrogenase complex (PDC). Flow cytometry showed that TGF-β1 reduced the PDC subunit PDH-E1α in fibroblasts derived from injured, but not normal kidneys. An increase in expression of PDH kinase 1 (PDK1), and reduction in the phosphatase PDP1, were commensurate with net phosphorylation and inactivation of PDC. Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation. The effect of TGF-β1 on PDC activity, acetyl-CoA, αSMA and pro-collagen I was also ameliorated by sodium dichloroacetate, a small molecule inhibitor of PDK. A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.
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