CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

Yoshimi Nakagawa, Aoi Satoh, Hitomi Tezuka, Song iee Han, Kenta Takei, Hitoshi Iwasaki, Shigeru Yatoh, Naoya Yahagi, Hiroaki Suzuki, Yasumasa Iwasaki, Hirohito Sone, Takashi Matsuzaka, Nobuhiro Yamada, Hitoshi Shimano

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARα. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3−/− mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara−/− mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than Ppara−/− mice suggesting importance of adipose PPARα for supply of FFA and hyperlipidemia in Creb3l3−/− mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPARα. Furthermore, as KD-fed Creb3l3−/− mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD.

Original languageEnglish
Article number39182
JournalScientific Reports
Volume6
Issue number1
DOIs
StatePublished - 2016/12/23

ASJC Scopus subject areas

  • General

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