Shimano Hitoshi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba.
Yakugaku Zasshi. 2015;135(9):1003-9. doi: 10.1248/yakushi.15-00175-1.
Recent studies suggest that chronic local inflammation and cellular stresses are the key steps in organ defects in obesity-related diseases such as atherosclerosis, diabetes, and fatty liver. We have shown that an excess energy state activates sterol regulatory element-binding protein (SREBP)-1c, a master transcription factor for fatty acid synthesis causing the accumulation of lipids leading to fatty liver, insulin resistance, insulin secretion defects, and dyslipidemia and we clarified their molecular mechanisms. Recently, we shifted focus to the quality aspect of accumulated lipids. It has long been known that saturated and poly-unsaturated fatty acids are atherogenic and anti-atherogenic, respectively. Besides desaturation, we found that the chain-length of fatty acids is another important factor. Elovl6 that we have cloned as an SREBP-1 target is a fatty acid elongase that catalises the last step of fatty acid synthesis. Elovl6 KO mice exhibit obesity and fatty liver on a high energy diet, but unexpectedly were immune to insulin resistance (Nat. Med., 13, 2007, Matsuzaka et al.), atherosclerosis (Arterioscler. Thromb. Vasc. Biol., 31, 2011, Saito et al.) and non-alcoholic steatohepatitis (NASH) pathology including liver damage, ROS, and fibrosis (Hepatology, 56, 2012, Matsuzaka et al.). Elovl6 is crucial for protection against lung fibrosis (Nat. Commun., 4, 2013, Sunaga et al.). These data implicate that fatty acid composition is a new therapeutic target for a variety of chronic metabolic diseases. In this symposium review, a novel strategy for the prevention of life-related diseases will be discussed in the standpoint of application of wet-dry fusion strategies for theoretical and medicinal chemistry.
近期研究表明，慢性局部炎症和细胞应激是肥胖相关疾病（如动脉粥样硬化、糖尿病和脂肪肝）中器官缺陷的关键步骤。我们已经证明，能量过剩状态会激活固醇调节元件结合蛋白（SREBP）-1c，这是一种脂肪酸合成的主要转录因子，会导致脂质积累，进而引发脂肪肝、胰岛素抵抗、胰岛素分泌缺陷和血脂异常，并且我们阐明了其分子机制。最近，我们将重点转向了积累脂质的质量方面。长期以来，人们已知饱和脂肪酸和多不饱和脂肪酸分别具有致动脉粥样硬化和抗动脉粥样硬化的作用。除了去饱和作用，我们发现脂肪酸的链长是另一个重要因素。我们克隆的作为SREBP-1靶点的Elovl6是一种脂肪酸延长酶，它催化脂肪酸合成的最后一步。Elovl6基因敲除小鼠在高能饮食下会出现肥胖和脂肪肝，但出乎意料的是，它们对胰岛素抵抗（《自然医学》，2007年第13卷，松坂等人）、动脉粥样硬化（《动脉硬化、血栓形成和血管生物学》，2011年第31卷，斋藤等人）以及包括肝损伤、活性氧和纤维化在内的非酒精性脂肪性肝炎（NASH）病理具有免疫力（《肝脏病学》，2012年第56卷，松坂等人）。Elovl6对于预防肺纤维化至关重要（《自然通讯》，2013年第4卷，砂名贺等人）。这些数据表明，脂肪酸组成是多种慢性代谢疾病的一个新的治疗靶点。在本次研讨会综述中，将从湿-干融合策略在理论化学和药物化学中的应用角度，讨论预防生活相关疾病的新策略。
