Increased flux through the mevalonate pathway mediates fibrotic repair without injury

• Published in: The Journal of clinical investigation 2019-11, Vol.129 (11), p.4962-4978
• Main Authors: 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, Carter, A Brent
• Format: Article
• Language: English
• Subjects: Acetyl Coenzyme A - genetics; Acetyl Coenzyme A - metabolism; Adolescent; Adult; Aged; Animals; Apoptosis; Biochemistry; Biomedical research; Breast cancer; Cysteine; Cystine; Female; Fibroblasts; Fibrosis; Gene expression; Genotype & phenotype; Guanosine triphosphatases; Humans; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Immune response; Innate immunity; Kinases; Lung diseases; Lungs; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Mevalonate pathway; Mevalonic acid; Mevalonic Acid - metabolism; Mice; Mice, Knockout; Middle Aged; Mitochondria; Neuropeptides - genetics; Neuropeptides - metabolism; Oxidation; Oxidation-Reduction; Oxidation-reduction reactions; Phenotypes; Phosphorylation; Polarization; Polyamines; Post-translational modifications; Proteins; Pulmonary fibrosis; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Respiratory tract diseases; Statins
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI127959

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.