Transgenic expression of mutant peroxisome proliferator-activated receptor gamma 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 PPARgamma are involved in its pathogenesis. Hepatic overexpression of PPARgamma1 in mice provokes steatosis, whereas liver-specific PPARgamma disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPARgamma functions as an aggravator of steatosis. In contrast, PPARalpha-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPARgamma with mutations in its C-terminal ligand-binding domain (L468A/E471A mutant PPARgamma1) have been reported as a constitutive repressor of both PPARalpha and PPARgamma activities in vitro. To elucidate the effect of co-suppression of PPARalpha and PPARgamma on steatosis, we generated mutant PPARgamma transgenic mice (Liver mt PPARgamma Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPARalpha and PPARgamma agonist-induced augmentation of the expression of downstream target genes of PPARalpha and PPARgamma, respectively, was significantly attenuated, suggesting PPARalpha and PPARgamma co-suppression in vivo. Suppression of PPARalpha and PPARgamma target genes was also observed in the fasted and high-fat-fed conditions. Liver mt PPARgamma Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet-induced steatosis. The opposite hepatic outcomes in Liver mt PPARgamma Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPARalpha and PPARgamma in 2 different types of nutritionally provoked steatosis.
Tanaka
Tomohiro
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
Masuzaki
Hiroaki
H
Ebihara
Ken
K
Ogawa
Yoshihiro
Y
Yasue
Shintaro
S
Yukioka
Hideo
H
Chusho
Hideki
H
Miyanaga
Fumiko
F
Miyazawa
Takashi
T
Fujimoto
Muneya
M
Kusakabe
Toru
T
Kobayashi
Nozomi
N
Hayashi
Tatsuya
T
Hosoda
Kiminori
K
Nakao
Kazuwa
K
D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D005215:Fasting; D005234:Fatty Liver / Q000209:etiology* / Q000503:physiopathology* / Q000517:prevention & control; D015870:Gene Expression / Q000502:physiology; D005799:Genes, Dominant; D006801:Humans; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000235:genetics; D015854:Up-Regulation
D004041:Dietary Fats; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000683:Serum Amyloid P-Component