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

26 Citations (Scopus)

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

Fingerprint

Fatty Liver
Fructose
Liver
Chemical activation
Proteins
Lipopolysaccharides
Triglycerides
Serum
Lipids
Palmitic Acid
Transcription Factor AP-1
Hep G2 Cells
Inbred C57BL Mouse
Infiltration
Genetic Promoter Regions
Protein Binding
Endotoxins
Intestines
Up-Regulation
Down-Regulation

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

Cite this

Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction. / Liu, Xijun; Xue, Ruyi; Ji, Lingling; Zhang, Xingwang; Wu, Jian; Gu, Jianxin; Zhou, Meiling; Chen, She.

In: Biochemical and Biophysical Research Communications, Vol. 450, No. 1, 18.07.2014, p. 117-123.

Research output: Contribution to journalArticle

Liu, Xijun ; Xue, Ruyi ; Ji, Lingling ; Zhang, Xingwang ; Wu, Jian ; Gu, Jianxin ; Zhou, Meiling ; Chen, She. / Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction. In: Biochemical and Biophysical Research Communications. 2014 ; Vol. 450, No. 1. pp. 117-123.
@article{1df1e650ec53467a85f488a74a38cd64,
title = "Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction",
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.",
keywords = "Adipose differentiation-related protein, Farnesoid X receptor, Fructose, Non-alcoholic fatty liver disease, WAY-362450",
author = "Xijun Liu and Ruyi Xue and Lingling Ji and Xingwang Zhang and Jian Wu and Jianxin Gu and Meiling Zhou and She Chen",
year = "2014",
month = "7",
day = "18",
doi = "10.1016/j.bbrc.2014.05.072",
language = "English (US)",
volume = "450",
pages = "117--123",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction

AU - Liu, Xijun

AU - Xue, Ruyi

AU - Ji, Lingling

AU - Zhang, Xingwang

AU - Wu, Jian

AU - Gu, Jianxin

AU - Zhou, Meiling

AU - Chen, She

PY - 2014/7/18

Y1 - 2014/7/18

N2 - 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.

AB - 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.

KW - Adipose differentiation-related protein

KW - Farnesoid X receptor

KW - Fructose

KW - Non-alcoholic fatty liver disease

KW - WAY-362450

UR - http://www.scopus.com/inward/record.url?scp=84904744146&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904744146&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2014.05.072

DO - 10.1016/j.bbrc.2014.05.072

M3 - Article

C2 - 24875360

AN - SCOPUS:84904744146

VL - 450

SP - 117

EP - 123

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -