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 beta 2 (RAR beta 2) and RAR gamma 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 RAR beta 2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of alpha-smooth muscle actin (alpha-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 (TNF alpha), interleukin 1 beta (IL-1 beta), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-beta 1 (TGF-beta 1), 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 RAR gamma agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-beta 1 levels. In conclusion, our data demonstrate that RAR beta 2 is an attractive target for development of NAFLD therapies. aEuro cent Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). aEuro cent Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. aEuro cent We show that an agonist for retinoic acid receptor-beta 2 (RAR beta 2), but not RAR gamma, mitigates HSC activation and NAFLD.