Transgenic expression of mutant peroxisome proliferator-activated receptor γ in liver precipitates fasting-induced steatosis but protects against high-fat diet-induced steatosis in mice

Steatosis is one of the most common liver diseases and is associated with the metabolic syndrome. A line of evidence suggests that peroxisome proliferator-activated receptor (PPAR)alpha and PPAR gamma are involved in its pathogenesis. Hepatic overexpression of PPAR gamma 1 in mice provokes steatosis, whereas liver-specific PPAR gamma disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPAR gamma functions as an aggravator of steatosis. In contrast, PPAR alpha-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPAR with mutations in its C-terminal ligand-binding domain (L468A/E471 A mutant PPAR gamma 1) have been reported as a constitutive repressor of both PPAR alpha and PPAR gamma activities in vitro. To elucidate the effect of cosuppression of PPAR alpha and PPAR gamma on steatosis, we generated mutant PPAR gamma transgenic mice (Liver mt PPAR gamma Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPAR alpha and PPAR gamma agonist-induced augmentation of the expression of downstream target genes of PPAR alpha and PPAR gamma respectively, was significantly attenuated, suggesting PPAR alpha and PPAR gamma cosuppression in vivo. Suppression of PPAR alpha and PPAR gamma target genes was also observed in the fasted and high-fat-fed conditions. Liver mt PPAR gamma Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet-induced steatosis. The opposite hepatic outcomes in Liver mt PPAR gamma Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPAR alpha and PPAR gamma in 2 different types of nutritionally provoked steatosis. (c) 2005 Elsevier Inc. All rights reserved.