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The roles of retinoids in nonalcoholic fatty liver disease (NAFLD) remain unclear and a better understanding may lead to therapies that prevent or limit NAFLD progression. We examined the actions of retinoic acid receptor (RAR) agonists- AM80 for RARαand AC261066 for RARβ2- in a murine model of NAFLD. We fed wild type C57Bl/6 mice a chow or a 45% high fat diet (HFD) for 12 weeks, followed by 4 additional weeks with the HFD+AM80; HFD +AC261066; or HFD. The HFD+AM80 group showed greater hyperglycemia and glucose intolerance compared to other groups. Histopathological evaluation of the livers showed the highest degree of steatosis, triglycerides levels, and inflammation, assessed by F4/80 staining, in the HFD+AM80-treated compared to the HFD, the HFD+AC261066, and chow-fed mice. Liver vitamin A (retinol (ROL)) and retinyl palmitate levels were markedly lower in all HFD groups compared to chow-fed controls. HFD+AC261066-treated mice showed higher levels of a key intracellular ROL transporter, retinol-binding protein-1 (RBP1) compared to the HFD and HFD+AM80 groups. In conclusion, these data demonstrate that the selective RARαagonist AM80 exacerbates HFD-induced NAFLD and hyperglycemia. These findings should inform future studies examining the therapeutic potential of RAR agonists in HFDrelated disorders.


This article was originally published in PLOS One, available at DOI:10.1371/journal. pone.0211071.

This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0.



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