Transforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production.
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.
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Recep
R
Nigdelioglu
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Robert B
RB
Hamanaka
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Angelo Y
AY
Meliton
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Erin
E
O'Leary
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Leah J
LJ
Witt
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Takugo
T
Cho
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Kaitlyn
K
Sun
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Catherine
C
Bonham
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
David
D
Wu
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Parker S
PS
Woods
Pathology.
Aliya N
AN
Husain
University of Chicago Proteomics Core Facility, The University of Chicago, Chicago, Illinois 60637 and.
Don
D
Wolfgeher
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and.
Nickolai O
NO
Dulin
the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
Navdeep S
NS
Chandel
From the Departments of Medicine, Section of Pulmonary and Critical Care Medicine, and gmutlu@medicine.bsd.uchicago.edu.
Gökhan M
GM
Mutlu
D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D012694:Serine; D003094:Collagen; D050543:Phosphoglycerate Dehydrogenase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human
collagen; fibrosis; glucose metabolism; glycolysis; serine