Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction

Xijun Liu, Ruyi Xue, Lingling Ji, Xingwang Zhang, Jian Wu, Jianxin Gu, Meiling Zhou, She Chen

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Fructose is a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Here we investigated whether WAY-362450 (WAY), a potent synthetic and orally active FXR agonist, protects against fructose-induced steatosis and the underlying mechanisms. C57BL/6J mice, fed 30% fructose for 8 weeks, were treated with or without WAY, 30 mg/kg, for 20 days. The elevation of serum and hepatic triglyceride in mice fed 30% fructose was reversed by WAY treatment. Histologically, WAY significantly reduced triglyceride accumulation in liver, attenuated microphage infiltration and protected the junction integrity in intestine. Moreover, WAY remarkably decreased portal endotoxin level, and lowered serum TNFα concentration. In lipopolysaccharide (LPS)-induced NAFLD model, WAY attenuated serum TNFα level. Moreover, WAY suppressed LPS-induced expression of hepatic lipid droplet protein adipose differentiation-related protein (ADRP), down-regulation of it in mice fed 30% fructose. Furthermore, WAY repressed lipid accumulation and ADRP expression in a dose-dependent manner in palmitic acid (PA)-treated HepG2 and Huh7 cells. WAY suppressed TNFα-induced ADRP up-regulation via competing with AP-1 for ADRP promoter binding region. Together, our findings suggest that WAY, an FXR agonist, attenuates liver steatosis through multiple mechanisms critically involved in the development of hepatosteatosis, and represents a candidate for NAFLD treatment.

Original languageEnglish (US)
Pages (from-to)117-123
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume450
Issue number1
DOIs
StatePublished - Jul 18 2014
Externally publishedYes

Keywords

  • Adipose differentiation-related protein
  • Farnesoid X receptor
  • Fructose
  • Non-alcoholic fatty liver disease
  • WAY-362450

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biochemistry
  • Biophysics

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