Increased flux through the mevalonate pathway mediates fibrotic repair without injury

Jennifer L. Larson-Casey, Mudit Vaid, Linlin Gu, Chao He, Guo Qiang Cai, Qiang Ding, Dana Davis, Taylor F. Berryhill, Landon S. Wilson, Stephen Barnes, Jeffrey D. Neighbors, Raymond J. Hohl, Kurt A. Zimmerman, Bradley K. Yoder, Ana Leda F. Longhini, Vidya Sagar Hanumanthu, Ranu Surolia, Veena B. Antony, A. Brent Carter

Research output: Contribution to journalArticle

Abstract

Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

Original languageEnglish (US)
Pages (from-to)4962-4978
Number of pages17
JournalJournal of Clinical Investigation
Volume129
Issue number11
DOIs
StatePublished - Nov 1 2019

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Mevalonic Acid
Prenylation
Idiopathic Pulmonary Fibrosis
Macrophages
Wounds and Injuries
Dimercaprol
Acetyl Coenzyme A
Monomeric GTP-Binding Proteins
Post Translational Protein Processing
Innate Immunity
Cysteine
Proteins
Fibroblasts
Phenotype
Gene Expression

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Larson-Casey, J. L., Vaid, M., Gu, L., He, C., Cai, G. Q., Ding, Q., ... Brent Carter, A. (2019). Increased flux through the mevalonate pathway mediates fibrotic repair without injury. Journal of Clinical Investigation, 129(11), 4962-4978. https://doi.org/10.1172/JCI127959
Larson-Casey, Jennifer L. ; Vaid, Mudit ; Gu, Linlin ; He, Chao ; Cai, Guo Qiang ; Ding, Qiang ; Davis, Dana ; Berryhill, Taylor F. ; Wilson, Landon S. ; Barnes, Stephen ; Neighbors, Jeffrey D. ; Hohl, Raymond J. ; Zimmerman, Kurt A. ; Yoder, Bradley K. ; Longhini, Ana Leda F. ; Hanumanthu, Vidya Sagar ; Surolia, Ranu ; Antony, Veena B. ; Brent Carter, A. / Increased flux through the mevalonate pathway mediates fibrotic repair without injury. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 11. pp. 4962-4978.
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abstract = "Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.",
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Larson-Casey, JL, Vaid, M, Gu, L, He, C, Cai, GQ, Ding, Q, Davis, D, Berryhill, TF, Wilson, LS, Barnes, S, Neighbors, JD, Hohl, RJ, Zimmerman, KA, Yoder, BK, Longhini, ALF, Hanumanthu, VS, Surolia, R, Antony, VB & Brent Carter, A 2019, 'Increased flux through the mevalonate pathway mediates fibrotic repair without injury', Journal of Clinical Investigation, vol. 129, no. 11, pp. 4962-4978. https://doi.org/10.1172/JCI127959

Increased flux through the mevalonate pathway mediates fibrotic repair without injury. / Larson-Casey, Jennifer L.; Vaid, Mudit; Gu, Linlin; He, Chao; Cai, Guo Qiang; Ding, Qiang; Davis, Dana; Berryhill, Taylor F.; Wilson, Landon S.; Barnes, Stephen; Neighbors, Jeffrey D.; Hohl, Raymond J.; Zimmerman, Kurt A.; Yoder, Bradley K.; Longhini, Ana Leda F.; Hanumanthu, Vidya Sagar; Surolia, Ranu; Antony, Veena B.; Brent Carter, A.

In: Journal of Clinical Investigation, Vol. 129, No. 11, 01.11.2019, p. 4962-4978.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased flux through the mevalonate pathway mediates fibrotic repair without injury

AU - Larson-Casey, Jennifer L.

AU - Vaid, Mudit

AU - Gu, Linlin

AU - He, Chao

AU - Cai, Guo Qiang

AU - Ding, Qiang

AU - Davis, Dana

AU - Berryhill, Taylor F.

AU - Wilson, Landon S.

AU - Barnes, Stephen

AU - Neighbors, Jeffrey D.

AU - Hohl, Raymond J.

AU - Zimmerman, Kurt A.

AU - Yoder, Bradley K.

AU - Longhini, Ana Leda F.

AU - Hanumanthu, Vidya Sagar

AU - Surolia, Ranu

AU - Antony, Veena B.

AU - Brent Carter, A.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

AB - Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

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