Frontiers in Pharmacology (Apr 2021)

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

  • Haoyang Ma,
  • Haoyang Ma,
  • Haoyang Ma,
  • Jiaye Liu,
  • Jiaye Liu,
  • Jiaye Liu,
  • Yang Du,
  • Yang Du,
  • Yang Du,
  • Shengnan Zhang,
  • Shengnan Zhang,
  • Shengnan Zhang,
  • Weidong Cao,
  • Weidong Cao,
  • Weidong Cao,
  • Zhanjun Jia,
  • Zhanjun Jia,
  • Zhanjun Jia,
  • Wei Gong,
  • Wei Gong,
  • Wei Gong,
  • Aihua Zhang,
  • Aihua Zhang,
  • Aihua Zhang,
  • Aihua Zhang

DOI
https://doi.org/10.3389/fphar.2021.626166
Journal volume & issue
Vol. 12

Abstract

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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.

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