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.
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xijun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Xue
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Ji
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xingwang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Key Laboratory of Molecular Virology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Radiology, Zhongshan Hospital of Fudan University, Shanghai Institute of Medical Imaging, Shanghai 200032, China. Electronic address: zhou.meiling@zs-hospital.sh.cn.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: shechen@fudan.edu.cn.
authors.forename: She
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control*; D015536:Down-Regulation / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D005632:Fructose; D007211:Indoles / Q000008:administration & dosage*; D008070:Lipopolysaccharides; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D000070780:Perilipin-2; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001381:Azepines; D005632:Fructose; D007211:Indoles; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D000070780:Perilipin-2; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000602983:Plin2 protein, mouse; C540004:WAY-362450
keywords: Adipose differentiation-related protein; Farnesoid X receptor; Fructose; Non-alcoholic fatty liver disease; WAY-362450