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.