Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Biol Chem. 2010 Apr 9;285(15):11681-91. doi: 10.1074/jbc.M109.096107. Epub 2010 Feb 9.
Sterol regulatory element-binding protein (SREBP)-1 is a key transcription factor for the regulation of lipogenic enzyme genes in the liver. Polyunsaturated fatty acids (PUFA) selectively suppress hepatic SREBP-1, but molecular mechanisms remain largely unknown. To gain insight into this regulation, we established in vivo reporter assays to assess the activities of Srebf1c transcription and proteolytic processing. Using these in vivo reporter assays, we showed that the primary mechanism for PUFA suppression of SREBP-1 is at the proteolytic processing level and that this suppression in turn decreases the mRNA transcription through lowering SREBP-1 binding to the SREBP-binding element on the promoter ("autoloop regulatory circuit"), although liver X receptor, an activator for Srebf1c transcription, is not involved in this regulation by PUFA. The mechanisms for PUFA suppression of SREBP-1 confirm that the autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis.
固醇调节元件结合蛋白-1（SREBP-1）是调节肝脏中脂肪酶基因的关键转录因子。多不饱和脂肪酸（PUFA）选择性地抑制肝 SREBP-1，但分子机制在很大程度上仍不清楚。为了深入了解这种调控机制，我们建立了体内报告基因检测系统来评估 Srebf1c 转录和蛋白水解加工的活性。利用这些体内报告基因检测系统，我们表明 PUFA 抑制 SREBP-1 的主要机制是在蛋白水解加工水平，这种抑制作用反过来又通过降低 SREBP-1 与启动子上的 SREBP 结合元件（“自环调控回路”）的结合来降低 SREBP-1 的 mRNA 转录，尽管肝 X 受体（Srebf1c 转录的激活剂）不参与 PUFA 的这种调控。PUFA 抑制 SREBP-1 的机制证实，转录的自环调节对于甘油三酯合成的营养调控至关重要。
