Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury

Abstract

Sepsis-associated liver dysfunction remains a challenge in clinical practice with high mortality and limited specific therapies. DY131 is a pharmacological agonist of the orphan receptor estrogen-related receptor (ERR) γ which plays a crucial role in regulating energy generation, oxidative metabolism, cell apoptosis, inflammatory responses, etc. However, its role in acute liver injury is unknown. In this study, we evaluated the effect of DY131 on lipopolysaccharide (LPS)-induced liver injury. Mice were pretreated with DY131 through intraperitoneal injection at a dose of 5 mg/kg/day for 3 days prior to LPS challenge (10 mg/kg). 24 h later, they were anesthetized and sacrificed. Blood and liver tissues were collected for further studies. In a separate experiment, mice were treated with saline (vehicle) or DY131 for 3 days to evaluate the toxicity of DY131. We found that ERRγ was downregulated in the liver tissues from LPS-treated mice. Pretreatment with DY131 ameliorated LPS-induced liver injury as demonstrated by reduced liver enzyme release (ALT, AST, and LDH), improved liver morphological damage, and attenuated oxidative stress, inflammation and apoptosis. Meanwhile, DY131 had no significant side effects on hepatic and renal functions in mice. Finally, transcriptomics analysis revealed that the dysregulated pathways associated with inflammation and metabolism were significantly reversed by DY131 in LPS-treated mice, providing more evidence in favor of the protective effect of DY131 against LPS-induced liver injury. Altogether, these findings highlighted the protective effect of DY131 on LPS-induced hepatotoxicity possibly via suppressing oxidative stress, inflammation, and apoptosis.

Integrative Analysis of Transcriptome and Metabolome to Illuminate the Protective Effects of Didymin against Acute Hepatic Injury

“…Didymin, also known as isosakuranetin-7-O-rutinoside, is a common flavonoid found in many kinds of herbs, such as Origanum vulgare L. [ 12 ]. Didymin has been proven to be a potent antioxidant and possesses therapeutic effects on several types of tumors, such as lung cancer, breast cancer, and brain tumor [ 13 ]. In our previous study, we found that didymin could ameliorate dexamethasone-induced nonalcoholic fatty liver disease in C57BL/6J mice [ 14 ], suggesting that didymin might have the potential for the treatment of liver steatosis.…”

RNA-Sequencing Characterization of lncRNA and mRNA Functions in Septic Pig Liver Injury

“…LPS induces acute liver injury through inflammation and oxidative stress and is an important initiator of sepsis [ 11 , 12 ]. Previous studies have used a septic animal model induced by LPS to evaluate mechanisms and therapeutic strategies for sepsis-induced liver injury [ 13 ]. While the role of lncRNAs during liver disease has been extensively studied in humans, mice, and rats, little is currently known about their functional importance during LPS-induced hepatic injury in pigs, which are an ideal model species for studying human disease due to similar organ size and physiology [ 14 ].…”