@article{23ead60910934cdfa9e79af5361933aa,
title = "Increased flux through the mevalonate pathway mediates fibrotic repair without injury",
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.",
author = "Larson-Casey, {Jennifer L.} and Mudit Vaid and Linlin Gu and Chao He and Cai, {Guo Qiang} and Qiang Ding and Dana Davis and Berryhill, {Taylor F.} and Wilson, {Landon S.} and Stephen Barnes and Neighbors, {Jeffrey D.} and Hohl, {Raymond J.} and Zimmerman, {Kurt A.} and Yoder, {Bradley K.} and Longhini, {Ana Leda F.} and Hanumanthu, {Vidya Sagar} and Ranu Surolia and Antony, {Veena B.} and {Brent Carter}, A.",
note = "Funding Information: Chrysotile asbestos was a gift from Peter S. Thorne (University of Iowa, Iowa City, Iowa). Research reported in this publication was supported by NIH grants (2R01ES015981-12, 1R56ES027464-01, and 1 I01 CX001715-01, to ABC) from the Department of Veteran Affairs and a Parker B. Francis fellowship and American Lung Association grant (RG-507440, to JLC). Support for the Comprehensive Flow Cytometry Core was provided by NIH grants (P30AR048311 and P30AI27667). The AB SCIEX 6500 mass spectrometer in the Targeted Metabolomics and Proteomics Laboratory was purchased with funds provided by the UAB Health Services Foundation General Endowment Fund and operational funds from the UAB O{\textquoteright}Brien Acute Kidney Injury Center (P30DK079337) and the UAB Lung Health Center. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",
year = "2019",
month = nov,
day = "1",
doi = "10.1172/JCI127959",
language = "English (US)",
volume = "129",
pages = "4962--4978",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",
}