PPARγ Alleviates Sepsis-Induced Liver Injury by Inhibiting Hepatocyte Pyroptosis via Inhibition of the ROS/TXNIP/NLRP3 Signaling Pathway

Abstract

Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts anti-inflammatory and antioxidative properties. To investigate the potential effects of PPARγ on sepsis-induced liver injury and determine the related mechanisms, C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to create a sepsis model which was treated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulation of PPARγ decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and liver pathological damage and improved the 5-day survival rate. Increased expression of PPARγ also decreased sepsis-induced reactive oxygen species (ROS) by promoting the expression of Nrf2. In addition, upregulated PPARγ inhibited the expression of the TXNIP/NLRP3 signaling pathway by reducing ROS-induced injury in the liver during sepsis, which further reduced NLRP3-mediated pyroptosis and the inflammatory response. The role of PPARγ was further examined in in vitro experiments, where lipopolysaccharide- (LPS-) treated HepG2 and Hep3B cells were incubated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulated PPARγ ameliorated LDH release and improved cell viability. Our results indicated that increased expression of PPARγ reduced ROS levels and inhibited the TXNIP/NLRP3 signaling pathway, resulting in decreased pyroptosis and reduced liver dysfunction during sepsis.

Activation of LRP1 ameliorates cerebral ischemia/reperfusion injury and cognitive decline by suppressing neuroinflammation and oxidative stress through TXNIP/NLRP3 signaling pathway in mice

“…At the same time, TXNIP can directly bind to NLRP3 and activate the NLRP3 inflammasome, further aggravating oxidative stress [22]. Previous studies have also demonstrated that the regulation of NLRP3 by TXNIP is dependent on ROS [47,48]. In this study, it was found that the decrease and increase of TXNIP correspond to the decrease and increase of oxidative stress, respectively.…”

Altered intestinal microbiome and metabolome correspond to the clinical outcome of sepsis

“…Bacteroides species gathered in Cluster 3 and interacted with a few genes from Cluster B outstandingly. Among these gene interactions, Mmp9, a well-studied metalloprotease involved in barrier disruption, was positively correlated with Bacteroides species, while Cth, which encodes cystathionine-γ-lyase, a major endogenous hydrogen sulfide-producing enzyme shown to suppress inflammation through IL-8 signaling [ 22 , 23 ], was negatively correlated. Correlation analysis of the ileum also revealed three main bacterial clusters and three gene clusters (Additional file 6 : Figure S4C).…”

Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP/NLRP3 Signaling Pathway in Mice

“…At the same time, TXNIP can directly bind to NLRP3 and activate the NLRP3 inflammasome, further aggravating oxidative stress [ 22 ]. Previous studies have also demonstrated that the regulation of NLRP3 by TXNIP is dependent on ROS [ 47 , 48 ]. In this study, it was found that the decrease and increase of TXNIP correspond to the decrease and increase of oxidative stress, respectively.…”