Polyunsaturated Fatty Acids Selectively Suppress Sterol Regulatory Element-binding Protein-1 through Proteolytic Processing and Autoloop Regulatory Circuit
Polyunsaturated Fatty Acids Selectively Suppress Sterol Regulatory Element-binding Protein-1 through Proteolytic Processing and Autoloop Regulatory Circuit
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DOI：
10.1074/jbc.m109.096107
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发表时间：
2010-04-09
影响因子：
4.8
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Takeuchi, Yoshinori;Yahagi, Naoya;Shimano, Hitoshi
固醇调节元件结合蛋白（SREBP）-1是调节肝脏中脂肪生成酶基因的关键转录因子。多不饱和脂肪酸（PUFA）选择性抑制肝脏SREBP-1，但分子机制仍不清楚。为了深入了解这种调节，我们建立了体内报告基因测定来评估Srebf 1c转录和蛋白水解加工的活性。使用这些体内报告基因测定，我们表明PUFA抑制SREBP-1的主要机制是在蛋白水解加工水平，这种抑制反过来又通过降低SREBP-1与启动子上SREBP结合元件的结合来降低mRNA转录（“自动环调节回路”），尽管肝脏X受体（Srebf 1c转录的激活剂）不参与PUFA的这种调节。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节至关重要。
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.