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Dual Outcomes of Rosiglitazone Treatment on Fatty Liver

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Abstract

In previous studies, it has been reported that rosiglitazone has opposing effects on nonalcoholic fatty liver disease. The purpose of the current study is to test the hypothesis that such opposing effects are related to different levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the liver. Using a gene transfer approach and mice fed a high-fat diet (HFD) as an animal model, we demonstrate that mice with low levels of PPAR-γ expression in the liver are resistant to HFD-induced development of fatty liver when treated with rosiglitazone. Conversely, rosiglitazone treatment actually exacerbates liver steatosis in obese mice that have a higher level of PPAR-γ. Mechanistic studies show that an elevated hepatic PPAR-γ level is associated with an increased expression of genes responsible for lipid metabolism in the liver, particularly Cd36, Fabp4, and Mgat1. The concurrent transfer of these three genes into the mouse liver fully recapitulates the phenotypic change induced by the overexpression of PPAR-γ. These results provide evidence in support of the importance of PPAR-γ in the liver when rosiglitazone is considered for the treatment of fatty liver disease. Clinically, our results suggest the necessity of verifying PPAR-γ levels in the liver when rosiglitazone is considered as a treatment option, and indicate that the direct use of rosiglitazone for treatment of nonalcoholic fatty liver may not be desirable when the patient’s PPAR-γ level in the liver is significantly elevated.

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Acknowledgments

The study was supported in part by grants from NIH (RO1EB007357 and RO1HL098295). We thank Dr. Megan Morgan for proofreading this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA

    Mingming Gao, Yongjie Ma, Mohammad Alsaggar & Dexi Liu

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  1. Mingming Gao
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Correspondence to Dexi Liu.

Ethics declarations

Animal treatments were performed following the approved protocol (A2014 07-008-Y1-A0) by the IACUC of the University of Georgia.

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The authors declare that they have no conflicts of interest.

Electronic Supplementary Material

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Supplementary Figure 1

Rosiglitazone alleviated HFD-induced hepatic fat accumulation in lean mice. (A) Representative images of the liver after treatment with or without rosiglitazone; (B) Liver weight; (C) Liver triglyceride level. Values in (B) and (C) represent average ± SD (n = 5). * p < 0.05, and ** p < 0.01 compared with control mice. (TIF 5581 kb)

Supplementary Figure 2

PPAR-γ and lipid droplets co-localize in liver hepatocytes post hydrodynamic gene transfer. The red dots indicate lipid droplets in the cytoplasm and the green dots (pointed by the yellow arrows) indicate presence of PPAR-γ in the nucleus. (TIF 5137 kb)

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Gao, M., Ma, Y., Alsaggar, M. et al. Dual Outcomes of Rosiglitazone Treatment on Fatty Liver. AAPS J 18, 1023–1031 (2016). https://doi.org/10.1208/s12248-016-9919-9

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  • DOI: https://doi.org/10.1208/s12248-016-9919-9

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