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

Tomohiro Tanaka, Hiroaki Masuzaki, Ken Ebihara, Yoshihiro Ogawa, Shintaro Yasue, Hideo Yukioka, Hideki Chusho, Fumiko Miyanaga, Takashi Miyazawa, Muneya Fujimoto, Toru Kusakabe, Nozomi Kobayashi, Tatsuya Hayashi, Kiminori Hosoda, Kazuwa Nakao

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

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 PPARγ are involved in its pathogenesis. Hepatic overexpression of PPARγ1 in mice provokes steatosis, whereas liver-specific PPARγ disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPARγ functions as an aggravator of steatosis. In contrast, PPARα-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPARγ with mutations in its C-terminal ligand-binding domain (L468A/E471A mutant PPARγ1) have been reported as a constitutive repressor of both PPARα and PPARγ activities in vitro. To elucidate the effect of cosuppression of PPARα and PPARγ on steatosis, we generated mutant PPARγ transgenic mice (Liver mt PPARγ Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPARα and PPARγ agonist-induced augmentation of the expression of downstream target genes of PPARα and PPARγ, respectively, was significantly attenuated, suggesting PPARα and PPARγ cosuppression in vivo. Suppression of PPARα and PPARγ target genes was also observed in the fasted and high-fat-fed conditions. Liver mt PPARγ Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet-induced steatosis. The opposite hepatic outcomes in Liver mt PPARγ Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPARα and PPARγ in 2 different types of nutritionally provoked steatosis.

Original languageEnglish
Pages (from-to)1490-1498
Number of pages9
JournalMetabolism: Clinical and Experimental
Volume54
Issue number11
DOIs
Publication statusPublished - Nov 1 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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