15‐PGDH Prevents LPS‐induced Acute Liver Injury through Activation PPAR‐γ

Abstract

The NAD+‐dependent 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) catalyzes the oxidation of Prostaglandin E2 (PGE2), converts PGE2 to 15‐keto‐PGE2 (an endogenous ligand for peroxisome proliferator‐activated receptor‐gamma [PPAR‐γ]). PPAR‐γ is a ligand‐dependent transcriptional factor, which controls genes relevant to the regulation of liver cytokines production and hepatocyte apoptosis. To evaluate the significance of 15‐PGDH/PPAR‐γ cascade in hepatocyte apoptosis and liver injury, we generated transgenic mice with targeted expression of 15‐PGDH in the liver by using an albumin promoter‐enhancer–driven vector and the animals were subjected to lipopolysaccharide (LPS)‐induced acute liver injury. Specifically, the 15‐PGDH transgenic (Tg) and wild type mice were administered intraperitoneally with LPS (60ng/g) in combination with D‐galactosamine (D‐GalN) (800µg/g) for 5 hours and the extent of liver injury was assessed by histopathology, serum aminotransferases, caspase‐3 staining, and caspase activation. Comparing to wild type mice, the 15‐PGDH Tg mice exhibited lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, less liver damage, and less hepatocyte apoptosis, and the 15‐PGDH Tg livers showed reduced production of inflammatory cytokines and reactive oxygen species (ROS), higher PPAR‐γ downstream gene expression, and weaker activation of TNF‐α/JNK cascade compared. Pretreatment 15‐PGDH Tg mice with inhibitor/antagonist of 15‐PGDH/PPAR‐γ restored the susceptibility of 15‐PGDH Tg mice to LPS‐induced acute liver injury. Our findings suggest that 15‐PGDH ameliorates LPS‐induced liver injury through its enzymatic product, 15‐keto‐PGE2, which activates PPAR‐γ and thus inhibits ROS and TNF‐α/JNK cascades.