Peroxisome proliferator-activated receptor-α accelerates α-chlorofatty acid catabolism

Palladino, Elisa N.D.; Wang, Wenyi; Albert, Carolyn J.; Langhi, Cédric; Baldán, Ángel; Ford, David A.

doi:10.1194/jlr.m069740

Cited by 10 publications

(8 citation statements)

References 39 publications

(35 reference statements)

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“…The PPAR pathway family, which includes the PPAR Alpha pathway, the PPAR Beta pathway, and the PPAR Gamma pathway, plays a key role in substance metabolism (including glucose metabolism, lipid metabolism, and protein metabolism). Specifically, PPAR Alpha was a core factor for fatty acid oxidation in liver, which was activated by ligands or drugs such as fibrates, resulting in a decrease in serum level of TG [ 54 ]. PPAR Gamma was also an important factor for the etiology of IR [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Multivariate analysis of genomics data to identify potential pleiotropic genes for type 2 diabetes, obesity and dyslipidemia using Meta-CCA and gene-based approach

Chen

Zhang

et al. 2018

PLoS ONE

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Previous studies have demonstrated the genetic correlations between type 2 diabetes, obesity and dyslipidemia, and indicated that many genes have pleiotropic effects on them. However, these pleiotropic genes have not been well-defined. It is essential to identify pleiotropic genes using systematic approaches because systematically analyzing correlated traits is an effective way to enhance their statistical power. To identify potential pleiotropic genes for these three disorders, we performed a systematic analysis by incorporating GWAS (genome-wide associated study) datasets of six correlated traits related to type 2 diabetes, obesity and dyslipidemia using Meta-CCA (meta-analysis using canonical correlation analysis). Meta-CCA is an emerging method to systematically identify potential pleiotropic genes using GWAS summary statistics of multiple correlated traits. 2,720 genes were identified as significant genes after multiple testing (Bonferroni corrected p value < 0.05). Further, to refine the identified genes, we tested their relationship to the six correlated traits using VEGAS-2 (versatile gene-based association study-2). Only the genes significantly associated (Bonferroni corrected p value < 0.05) with more than one trait were kept. Finally, 25 genes (including two confirmed pleiotropic genes and eleven novel pleiotropic genes) were identified as potential pleiotropic genes. They were enriched in 5 pathways including the statin pathway and the PPAR (peroxisome proliferator-activated receptor) Alpha pathway. In summary, our study identified potential pleiotropic genes and pathways of type 2 diabetes, obesity and dyslipidemia, which may shed light on the common biological etiology and pathogenesis of these three disorders and provide promising insights for new therapies.

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Section: Discussionmentioning

confidence: 99%

Multivariate analysis of genomics data to identify potential pleiotropic genes for type 2 diabetes, obesity and dyslipidemia using Meta-CCA and gene-based approach

Chen

Zhang

et al. 2018

PLoS ONE

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“…A reporter gene system was used to identify 2-ClFA as a stimulator of PPAR-α activity. These findings were confirmed in primary murine hepatocytes treated with 2-ClFA, where an increase in the expression of PPAR-α target genes was observed [57].…”

Section: Clearance Of Chlorinated Lipidsmentioning

confidence: 63%

“…Recent studies demonstrated that 2-ClFA clearance is accelerated by treatment with the peroxisome proliferator-activated receptor (PPAR)-α agonist WY14643, which increases the enzymatic machinery responsible for hepatic ω-oxidation [57]. While primary hepatocytes isolated from wild-type mice treated with WY14643 display accelerated 2-ClFA ω-oxidation, those from PPAR-α −/− mice did not respond to treatment with WY14643 to accelerate 2-ClFA ω-oxidation.…”

Section: Clearance Of Chlorinated Lipidsmentioning

confidence: 99%

“…To assess the effects of PPAR-α activity in vivo , wild-type and PPAR-α −/− mice were injected with stable-isotope labeled 2-ClFA. Mass spectrometric analyses demonstrated that PPAR-α −/− mice had higher levels of 2-ClFA in the plasma and lower levels of 2-chloroadipic acid in the urine compared to wild-type mice [57]. These results indicate that, in the absence of PPAR-α activity, catabolism of 2-ClFA is reduced, resulting in accumulation in systemic blood.…”

Section: Clearance Of Chlorinated Lipidsmentioning

confidence: 99%

“…Further analysis also revealed increased levels of 2-ClFA in the liver of PPAR-α −/− mice, suggesting that catabolism of 2-ClFA occurs in hepatocytes. Interestingly, further studies conducted in both HepG2 and primary murine hepatocytes showed that 2-ClFA functions as a lipid ligand for PPAR-α [57]. A reporter gene system was used to identify 2-ClFA as a stimulator of PPAR-α activity.…”

Section: Clearance Of Chlorinated Lipidsmentioning

confidence: 99%

See 2 more Smart Citations

The chlorinated lipidome originating from myeloperoxidase-derived HOCl targeting plasmalogens: Metabolism, clearance, and biological properties

Palladino

Hartman

Albert

et al. 2018

Archives of Biochemistry and Biophysics

Self Cite

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Myeloperoxidase produces the two-electron oxidant HOCl, which targets plasmalogen phospholipids liberating 2-chlorofatty aldehyde. 2-Chlorofatty aldehyde has four known fates: 1) oxidation to 2-chlorofatty acid; 2) reduction to 2-chlorofatty alcohol; 3) Schiff base adduct formation with proteins and amines; and 4) reactivity with glutathione through nucleophilic attack of the α-chlorinated carbon. 2-Chlorofatty acid does not undergo conventional fatty acid β-oxidation due to the presence of the α-chlorinated carbon; however, 2-chlorofatty acid does undergo sequential ω-oxidation and β-oxidation from the ω-end, ultimately resulting in 2-chloroadipic acid urinary excretion. Recent studies have demonstrated that 2-chlorofatty acid clearance is increased by treatment with the PPAR-α agonist WY14643, which increases the enzymatic machinery responsible for hepatic ω-oxidation. Furthermore, 2-chlorofatty acid has been shown to be a PPAR-α agonist, and thus accelerates its own clearance. The roles of 2-chlorofatty aldehyde and 2-chlorofatty acid on leukocyte and endothelial function have been explored by several groups, suggesting that chlorinated lipids induce endothelial cell dysfunction, neutrophil chemotaxis, monocyte apoptosis, and alterations in vascular tone. Thus, the chlorinated lipidome, produced in response to leukocyte activation, is a potential biomarker and therapeutic target to modulate host response in inflammatory diseases.

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Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease

Kim

Shapiro

Cottrill

et al. 2023

Free Radical Biology and Medicine

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Peroxisome proliferator-activated receptor-α accelerates α-chlorofatty acid catabolism

Cited by 10 publications

References 39 publications

Multivariate analysis of genomics data to identify potential pleiotropic genes for type 2 diabetes, obesity and dyslipidemia using Meta-CCA and gene-based approach

Multivariate analysis of genomics data to identify potential pleiotropic genes for type 2 diabetes, obesity and dyslipidemia using Meta-CCA and gene-based approach

The chlorinated lipidome originating from myeloperoxidase-derived HOCl targeting plasmalogens: Metabolism, clearance, and biological properties

Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease

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