Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Sci Rep. 2016 Dec 16;6:39182. 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.
CREB3L3 与 PPARα 相互作用，参与脂肪酸氧化和酮体生成。为了评估相对贡献，研究了敲除和转基因小鼠的组合。在强调肝酮生成能力的生酮饮食（KD）中，Creb3l3 小鼠表现出与 Ppara 小鼠相当的脂肪酸氧化和酮体生成基因表达减少。在双敲除小鼠中，大多数基因进一步受到抑制，表明肝 CREB3L3 的独立贡献。在禁食期间，酮体生成对 CREB3L3 的依赖性比 Ppara 小鼠小，这表明脂肪组织 PPARα 对 FFA 的供应和 Creb3l3 小鼠的高脂血症很重要。总之，CREB3L3 通过两种途径在肝脏对能量饥饿的适应中发挥关键作用：直接相关的基因调控和 PPARα 的自动循环激活。此外，由于 KD 喂养的 Creb3l3 小鼠表现出严重的脂肪肝、激活炎症，因此 CREB3L3 可能是 NAFLD 的治疗靶点。
