New therapeutic strategy toward circadian dysrhythmia induced NAFLD

• Project/Area Number: 16K19356
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Yokohama City University
• Principal Investigator: FUJITA KOJI 横浜市立大学, 附属病院, 講師 (30468160)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 概日リズム障害 / 時計遺伝子 / 胃排泄障害 / 脂質代謝障害 / NAFLD / 胃排泄能の遅延 / オレキシン受容体拮抗薬

Outline of Final Research Achievements

Irregular circadian rhythm modulated diurnal variation of the clock gene RORA expression which closely related to lipid metabolism. The expression of the lipid synthesis gene that should be suppressed during the dormant period was promoted, lead to induce fatty liver and abnormal lipid metabolism in animal models. It was also confirmed the expression of lipid metabolism-related genes during dormancy was suppressed by suppressing RORA expression using siRNA. I regret to find that the melatonin/orexin agonists and PPAR agonists, which were thought to be related to the regulation of RORA expression, could not have the effect of regulating RORA expression or improving fatty liver. The elucidation of the new mechanism could reveal the new therapeutic strategy for NAFLD caused by circadian rhythm disorder.

Academic Significance and Societal Importance of the Research Achievements

就労人口の約20％がシフトワーカーであり、かつNAFLD罹患率が成人の約20％である事から、 シフトワーカーNAFLDは成人人口のおよそ5％前後（300万人強）存在すると示唆される。その他にも近年、特に都会を中心に照明過多に伴う睡眠障害患者は急増しており、難治性である概日リズム障害起因性NAFLDも相当数潜在している事が予想される。極度の生活習慣病と言える概日リズム障害起因性NAFLDに対し，そのメカムズムの不透明性からこれまで薬物介入は困難であったが，メカニズムの一端を解明した事により、既存薬の応用や創薬に繋げる初動研究としての意義は大きいものと考える．