脂質の質に視点をおいた臓器障害治療戦略と創薬：SREBP-1cとElovl6

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  • 島野 仁
    筑波大学医学医療系内分泌代謝・糖尿病内科

書誌事項

タイトル別名
  • SREBP-1c and Elovl6 as Targets for Obesity-related Disorders
  • Symposium Review 脂質の質に視点をおいた臓器障害治療戦略と創薬 : SREBP-1cとElovl6
  • Symposium Review シシツ ノ シツ ニ シテン オ オイタ ゾウキ ショウガイ チリョウ センリャク ト ソウヤク : SREBP-1c ト Elovl6

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抄録

  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.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 135 (9), 1003-1009, 2015-09-01

    公益社団法人 日本薬学会

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