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

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.

[1]  S. Dai,et al.  Danshen Attenuates Intervertebral Disc Degeneration via Antioxidation in SD Rats , 2020, Oxidative medicine and cellular longevity.

[2]  R. Yao,et al.  Publication Trends of Research on Sepsis and Host Immune Response during 1999-2019: A 20-year Bibliometric Analysis , 2020, International journal of biological sciences.

[3]  Xi-Hong Li,et al.  Recombinant CC16 inhibits NLRP3/caspase-1-induced pyroptosis through p38 MAPK and ERK signaling pathways in the brain of a neonatal rat model with sepsis , 2019, Journal of Neuroinflammation.

[4]  F. Petronilho,et al.  The NLRP3 Inflammasome and Its Role in Sepsis Development , 2019, Inflammation.

[5]  Jingyao Zhang,et al.  Methane-Rich Saline Counteracts Cholestasis-Induced Liver Damage via Regulating the TLR4/NF-κB/NLRP3 Inflammasome Pathway , 2019, Oxidative medicine and cellular longevity.

[6]  Jingyao Zhang,et al.  Methane Alleviates Acetaminophen-Induced Liver Injury by Inhibiting Inflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Apoptosis through the Nrf2/HO-1/NQO1 Signaling Pathway , 2019, Oxidative medicine and cellular longevity.

[7]  A. Cataldi,et al.  PPAR-γ agonist GL516 reduces oxidative stress and apoptosis occurrence in a rat astrocyte cell line , 2019, Neurochemistry International.

[8]  Qing-Qing Wu,et al.  STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3 , 2019, Redox biology.

[9]  Jingyao Zhang,et al.  Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: in vivo and in vitro experiments , 2019, Aging.

[10]  Rongqian Wu,et al.  Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress , 2018, Redox biology.

[11]  Jingyao Zhang,et al.  Methane-Rich Saline Protects Against Sepsis-Induced Liver Damage by Regulating The PPAR-γ/NF-κB Signaling Pathway. , 2019, Shock.

[12]  Jingyao Zhang,et al.  Methane-Rich Saline Ameliorates Sepsis-Induced Acute Kidney Injury through Anti-Inflammation, Antioxidative, and Antiapoptosis Effects by Regulating Endoplasmic Reticulum Stress , 2018, Oxidative medicine and cellular longevity.

[13]  Jing Wu,et al.  NLRP3/Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy , 2018, Inflammation.

[14]  Jin-jian Lu,et al.  Diethyl Blechnic, a Novel Natural Product Isolated from Salvia miltiorrhiza Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2 , 2018, International journal of molecular sciences.

[15]  Seema Patel Inflammasomes, the cardinal pathology mediators are activated by pathogens, allergens and mutagens: A critical review with focus on NLRP3. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[16]  Niranjan Kissoon,et al.  Recognizing Sepsis as a Global Health Priority - A WHO Resolution. , 2017, The New England journal of medicine.

[17]  Wenqing Gao,et al.  Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. , 2017, Trends in biochemical sciences.

[18]  Jiangjuan Shao,et al.  ROS-JNK1/2-dependent activation of autophagy is required for the induction of anti-inflammatory effect of dihydroartemisinin in liver fibrosis. , 2016, Free radical biology & medicine.

[19]  Haichao Wang,et al.  PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation , 2016, Nature Communications.

[20]  Yizhi Yu,et al.  Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge , 2016, Scientific Reports.

[21]  Meng Li,et al.  Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation. , 2015, Antioxidants & redox signaling.

[22]  Bertrand Friguet,et al.  NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases , 2015, Redox biology.

[23]  C. Thiemermann,et al.  Refinement of Animal Models of Sepsis and Septic Shock , 2015, Shock.

[24]  G. Van den Berghe,et al.  Cholestatic liver (dys)function during sepsis and other critical illnesses , 2015, Intensive Care Medicine.

[25]  Michelle R. Campbell,et al.  Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha , 2012, Nucleic acids research.

[26]  Xiangmei Zhou,et al.  A role for mitochondria in NLRP3 inflammasome activation , 2011, Nature.

[27]  J. Schug,et al.  Re-expression of GATA2 Cooperates with Peroxisome Proliferator-activated Receptor-γ Depletion to Revert the Adipocyte Phenotype* , 2009, Journal of Biological Chemistry.

[28]  N. Gedik,et al.  Rosiglitazone, a PPAR-γ ligand, protects against burn-induced oxidative injury of remote organs , 2007 .