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

Zeyu Li,Tong Liu,Cong Wang,Kai Qu,Ruixia Cui,Chang Liu,Yang Feng,Yifan Jia,Yingmu Tong,Jingyao Zhang

doi:10.1155/2022/1269747

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.

Highlights

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is a major global public health challenge [1]
To explore the effect of Peroxisome proliferator-activated receptor Nrf2 (PPARγ) on septic liver damage, blood samples and liver tissue were collected for liver function determination and histological evaluation
It is noteworthy that upregulation of PPARγ by GW1929 attenuated the pathological changes in the liver

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is a major global public health challenge [1]. As one of the most vulnerable organs, the liver can be damaged at any stage during sepsis. Severe liver dysfunction often results in a poor prognosis during sepsis [2]. The mechanism of sepsis-induced liver injury is complex and involves many signaling pathways. Overproduction of reactive oxygen species (ROS), induced by mitochondrial dysfunction, is thought to play an important role in the pathogenesis of many different diseases, such as organ dysfunction in sepsis [3,4,5]. ROS can directly damage cells or tissues and indirectly activate a series of damage-related signaling pathways [6, 7]. Recent studies have revealed that ROS is a fundamental factor in triggering pyroptosis by activating the NOD-like receptor 3 (NLRP3) inflammasome [8, 9]

Objectives

Methods

Results

Discussion

Conclusion