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.