CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

• Published in: Scientific reports 2016-12, Vol.6 (1), p.39182-39182, Article 39182
• Main Authors: Nakagawa, Yoshimi, Satoh, Aoi, Tezuka, Hitomi, Han, Song-iee, Takei, Kenta, Iwasaki, Hitoshi, Yatoh, Shigeru, Yahagi, Naoya, Suzuki, Hiroaki, Iwasaki, Yasumasa, Sone, Hirohito, Matsuzaka, Takashi, Yamada, Nobuhiro, Shimano, Hitoshi
• Format: Article
• Language: English
• Subjects: 38; 38/15; 42; 631/337/572/2102; 64/60; 692/163/2743/2037; Adenoviridae - genetics; Animals; Blood Glucose - analysis; Carnitine O-Palmitoyltransferase - chemistry; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein - deficiency; Cyclic AMP Response Element-Binding Protein - genetics; Diet, Ketogenic; Energy Metabolism; Fatty Acids - chemistry; Fatty Acids - metabolism; Fatty Liver - etiology; Fatty Liver - metabolism; Fibroblast Growth Factors - blood; Gene Expression; Humanities and Social Sciences; Lipid Peroxidation; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; multidisciplinary; Plasmids - genetics; Plasmids - metabolism; PPAR alpha - deficiency; PPAR alpha - genetics; Promoter Regions, Genetic; RNA, Messenger - metabolism; Science; Triglycerides - blood
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39182

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.