生活習慣病の発症機構と治療戦略 : 木を診て森を診よう！

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  • 小川 佳宏
    九州大学大学院医学研究院病態制御内科学分野 | 東京医科歯科大学大学院医歯学総合研究科分子内分泌代謝学分野

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タイトル別名
  • Molecular Mechanism of Lifestyle-related Diseases : See Both the Wood and Trees!
  • 生活習慣病の発症機構と治療戦略 : 木を診て森も診よう!
  • セイカツ シュウカンビョウ ノ ハッショウ キコウ ト チリョウ センリャク : キ オ ミテ モリ モ ミヨウ!

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Energy homeostasis is maintained locally through parenchymal-stromal cell interaction and systemically through metabolic organ network. In obese adipose tissue, saturated fatty acids, which are released as a danger signal from hypertrophied adipocytes, stimulates a pathogen sensor TLR4 in the infiltrating macrophages, thus establishing a vicious cycle between adipocytes and macrophages to stimulate adipose tissue inflammation. Histologically, macrophages aggregate to constitute crown-like structures (CLS), where they are thought to scavenge the residual lipid droplets of dead adipocytes. Free fatty acids, when released from obese visceral fat depots, are transported in large quantities to the liver via the portal vein, where they are accumulated as ectopic fat, thus developing non-alcoholic fatty liver disease (NAFLD). There is a unique histological feature termed “hepatic CLS (hCLS)” the non-alcoholic steatohepatitis (NASH) liver, where macrophages aggregate to surround dead hepatocytes with large lipid droplets. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. Our data suggest that hCLS serves as an origin of hepatic inflammation and fibrosis during the progression from simple steatosis to NASH. Sodium glucose cotransporter 2 (SGLT2) inhibitors, an oral antidiabetic drug, promotes the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. Inhibition of SGLT2 lowers is expected to reduce body weight because of urinary calorie loss. Interestingly, SGLT2 inhibition improves hepatic steatosis in obese mice irrespective of body weight reduction. There is an inverse correlation between liver weight and adipose tissue weight in obese mice with SGLT2 inhibition, suggesting that SGLT2 inhibition induces the “healthy” adipose tissue expansion and prevents ectopic fat accumulation in the liver. Our data suggest that seeing both the wood and trees is Required to understand the molecular mechanism of lifestyle-related diseases.

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