A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease.
Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies.



• Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). • Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. • We show that an agonist for retinoic acid receptor-β2 (RARβ2), but not RARγ, mitigates HSC activation and NAFLD.
Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Ave., New York, NY, 10065, USA.
Steven E
SE
Trasino
Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Ave., New York, NY, 10065, USA.
Xiao-Han
XH
Tang
Department of Pathology, Weill Cornell Medical College of Cornell University, 525 East 68th Street, New York, NY, 10065, USA.
Jose
J
Jessurun
Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Ave., New York, NY, 10065, USA. ljgudas@med.cornell.edu.
Lorraine J
LJ
Gudas
D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D059305:Diet, High-Fat; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009284:Naphthols / Q000494:pharmacology; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000097768:Retinoic Acid Receptor gamma
D001565:Benzoates; D016207:Cytokines; D009284:Naphthols; D018168:Receptors, Retinoic Acid; D013844:Thiazoles; D000097768:Retinoic Acid Receptor gamma; C507711:4-(4-(2-(n-butoxy)ethoxy)-5-methylthiazol-2-yl)-2-fluorobenzoic acid; C000591478:4-(6-hydroxy-7-tricyclo(3.3.1.13,7)dec-1-yl-2-naphthalenyl)benzoic acid; C082925:retinoic acid receptor beta
Retinoic acid; Retinoic acid receptor β2; Steatosis; Stellate cells