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

• Published in: Metabolism, clinical and experimental Vol. 54; no. 11; pp. 1490 - 1498
• Main Authors: Tanaka, Tomohiro, Masuzaki, Hiroaki, Ebihara, Ken, Ogawa, Yoshihiro, Yasue, Shintaro, Yukioka, Hideo, Chusho, Hideki, Miyanaga, Fumiko, Miyazawa, Takashi, Fujimoto, Muneya, Kusakabe, Toru, Kobayashi, Nozomi, Hayashi, Tatsuya, Hosoda, Kiminori, Nakao, Kazuwa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2005
• Subjects: Animals; Dietary Fats - pharmacology; Fasting; Fatty Liver - etiology; Fatty Liver - physiopathology; Fatty Liver - prevention & control; Gene Expression - physiology; Genes, Dominant; Humans; Liver - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; PPAR alpha - genetics; PPAR alpha - metabolism; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; RNA, Messenger - analysis; Serum Amyloid P-Component - genetics; Up-Regulation
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2005.05.015

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) α and PPAR γ are involved in its pathogenesis. Hepatic overexpression of PPAR γ1 in mice provokes steatosis, whereas liver-specific PPAR γ disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPAR γ functions as an aggravator of steatosis. In contrast, PPAR α-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPAR γ with mutations in its C-terminal ligand-binding domain (L468A/E471A mutant PPAR γ1) have been reported as a constitutive repressor of both PPAR α and PPAR γ activities in vitro. To elucidate the effect of cosuppression of PPAR α and PPAR γ on steatosis, we generated mutant PPAR γ transgenic mice (Liver mt PPAR γ Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPAR α and PPAR γ agonist–induced augmentation of the expression of downstream target genes of PPAR α and PPAR γ, respectively, was significantly attenuated, suggesting PPAR α and PPAR γ cosuppression in vivo. Suppression of PPAR α and PPAR γ target genes was also observed in the fasted and high-fat–fed conditions. Liver mt PPAR γ Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet–induced steatosis. The opposite hepatic outcomes in Liver mt PPAR γ Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPAR α and PPAR γ in 2 different types of nutritionally provoked steatosis.