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The Peroxisome Proliferator-Activated Receptor ?- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) shows promising potential to enhance host defenses against Mycobacterium tuberculosis infection. Herein we evaluated the protective effect of PPAR? against nontuberculous mycobacterial (NTM) infections. Using a rapidly growing NTM species, Mycobacterium abscessus (Mabc), we found that the intracellular bacterial load and histopathological damage were increased in PPAR?-null mice in vivo. In addition, PPAR? deficiency led to excessive production of proinflammatory cytokines and chemokines after infection of the lung and macrophages. Notably, administration of gemfibrozil (GEM), a PPAR? activator, significantly reduced the in vivo Mabc load and inflammatory response in mice. Transcription factor EB was required for the antimicrobial response against Mabc infection. Collectively, these results suggest that manipulation of PPAR? activation has promising potential as a therapeutic strategy for NTM disease.

SUBMITTER: Kim YS

PROVIDER: S-EPMC7140404 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections.

Kim Yi Sak YS Kim Jin Kyung JK Hanh Bui Thi Bich BTB Kim Soo Yeon SY Kim Hyeon Ji HJ Kim Young Jae YJ Jeon Sang Min SM Park Cho Rong CR Oh Goo Taeg GT Park June-Woo JW Kim Jin-Man JM Jang Jichan J Jo Eun-Kyeong EK

Cells 20200306 3

Peroxisome proliferator-activated receptor α (PPARα) shows promising potential to enhance host defenses against Mycobacterium tuberculosis infection. Herein we evaluated the protective effect of PPARα against nontuberculous mycobacterial (NTM) infections. Using a rapidly growing NTM species, Mycobacterium abscessus (Mabc), we found that the intracellular bacterial load and histopathological damage were increased in PPARα-null mice in vivo. In addition, PPARα deficiency led to exces ...[more]

PMID: 32155958

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Dataset Information

The Peroxisome Proliferator-Activated Receptor ?- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections.

Publications

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against <i>Mycobacterium abscessus</i> Infections.

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