Yang_2016_Cell.Physiol.Biochem_38_696

BACKGROUND/AIMS: Comparative gene identification-58 (CGI-58), an adipose triglyceride lipase (ATGL) coactivator, strongly promotes ATGL-mediated triglyceride (TG) catabolism. Beyond its function in promoting lipolysis, other features of CGI-58 have been proposed. Here, we investigated the role of CGI-58 in the regulation of inflammatory responsiveness in macrophages.
METHODS: Macrophage-specific GCI-58 transgenic mice (TG) and wild type mice (WT) were fed a high fat diet (HFD), and RAW264.7 cells were treated with lipopolysaccharide (LPS). The peroxisome proliferator-activated receptor (PPAR) signaling was detected. The inflammatory responsiveness and mitochondrial function were examined.
RESULTS: TG mice showed lower serum levels of proinflammatory cytokines and better mitochondrial function in macrophages compared with WT control. Knockdown of CGI-58 in RAW264.7 cells aggravated LPS-induced inflammation and mitochondrial dysfunction. CGI-58 overexpression and silencing in macrophages induced and inhibited PPARx03B3; expression and activity, respectively. Most importantly, the PPARx03B3;-specific agonist rosiglitazone significantly suppressed inflammation and mitochondrial dysfunction induced by CGI-58 deficiency. Furthermore, knockdown of PPARx03B3; in macrophages significantly dampened the role of CGI-58 in suppression of inflammation and mitochondrial dysfunction. Interestingly, CGI-58 inhibited histone deacetylation and the recruitment of histone deacetylase (HDAC) to the PPARx03B3; promoter. Finally, ATGL deficiency did not affect inflammatory responsiveness and PPARx03B3; signaling in macrophages. CONCLUSION: These results demonstrate that macrophage CGI-58 enhances PPARx03B3; signaling and thus suppresses inflammatory responsiveness and mitochondrial dysfunction.