Figure 1.

Schematic representation of key metabolic adaptations in fibroblasts to support collagen synthesis. Metabolic and biosynthetic fates of (A) glucose and (B) glutamine highlight potential synthetic (arrow head) and regulatory (solid dot) functions in fibrogenesis. (C,D) Putative changes in metabolic flux caused by TGF-β1 are diagrammatically indicated by changes in arrow thickness. These include (C) a shift from oxidative phosphorylation to glycolysis with commensurate increases in amino acid and nucleotide synthesis and a reduction in Acetyl-CoA generation. Export of the end product lactate may also be pro-fibrotic as local changes to pH contribute to activation of latent TGF-β. (D) Parallel hypothesized TGF-β1 induced changes in glutamine metabolism both supplement amino acid synthesis and TCA intermediates lost through metabolic shifts in glucose metabolism. Key: Acetyl-CoA, Acetyl coenzyme-A; ASCT2, alanine-serine-cysteine transporter 2; αKG, α-ketoglutarate; ATP, adenosine triphosphate; ETC, electron transport chain; Gls, glutaminase; JMJD3, Jumonji domain-containing protein D3; OxPhos, oxidative phosphorylation; P4OH, prolyl-4-hydroxylase; P5CS, pyrroline-5-carboxylate synthase; P5C, pyrroline-5-carboxylate; PDC, pyruvate dehydrogenase complex; TCA, tricarboxylic acid cycle; TGF-β1, transforming growth factor-β1.