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A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease

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Abstract

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.

Key Messages

• 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.

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Acknowledgments

We thank Daniel Stummer for editorial assistance, Viral Patel for Q-PCR and laboratory assistance, and the Gudas lab for data discussions.

Financial support

This research was supported by Weill Cornell funds and by R01CA043796 to LJG. ST was supported by NCI TG CA062948 during a portion of this research.

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Authors and Affiliations

  1. Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Ave., New York, NY, 10065, USA

    Steven E. Trasino, Xiao-Han Tang & Lorraine J. Gudas

  2. Department of Pathology, Weill Cornell Medical College of Cornell University, 525 East 68th Street, New York, NY, 10065, USA

    Jose Jessurun

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  1. Steven E. Trasino
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  2. Xiao-Han Tang
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  3. Jose Jessurun
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  4. Lorraine J. Gudas
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Correspondence to Lorraine J. Gudas.

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Conflict of interest

Weill Cornell has filed a patent application on some of the intellectual property (IP) in this manuscript, and this IP was licensed to Sveikatal, Inc. LJG and XHT are founders and have financial interests in Sveikatal, Inc.

Author contributions

S.E.T. performed experiments, analyzed data, wrote the manuscript, reviewed/edited manuscript. X.H.T. performed experiments, wrote the manuscript, and reviewed/edited the manuscript. J.J. researched data and reviewed/edited manuscript. L.J.G. performed experiments, wrote the manuscript, and reviewed/edited manuscript. Dr. Lorraine Gudas is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.

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Trasino, S.E., Tang, XH., Jessurun, J. et al. A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease. J Mol Med 94, 1143–1151 (2016). https://doi.org/10.1007/s00109-016-1434-z

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  • DOI: https://doi.org/10.1007/s00109-016-1434-z

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