The role of HSP110 family, Apg-2 in NASH-related hepatic lipid and glucose metabolism.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09368
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: YAMAGUCHI KANJI 京都府立医科大学, 医学(系)研究科(研究院), 助教 (50381950)
• Research Collaborator: Itoh Katsuhiko 京都大学, 医学研究科, 教授 (90281097)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 脂肪肝炎 / 分子シャペロン / LKB1 / HSP110 / Apg-2

Outline of Final Research Achievements

Hsp110 family, Apg-2 has a chaperone-like activity similar to Hsp70. However, the physiological and pathological functions of Apg-2 in NAFLD remain unclear. We studied HFD-induced liver steatosis in Apg-2-deficient mice for clarifying the role of Apg-2 in NAFLD. HFD for 12 weeks induced obesity and liver steatosis in wild-type mice but not in Apg-2-deficient mice. HFD-induced elevation of serum t-cholesterol and ALT levels were improved with enhanced phosphorylation levels of AMPKα in Apg-2-deficient mice. Hepatic mRNA levels of SREBP1c, FAS, and ACC were also significantly decreased compared with wild-type mice. Liver-specific overexpression of Apg-2 in Apg-2-deficient mice restored obesity and liver steatosis by decreasing phosphorylated AMPKα and promoting LKB1 ubiquitination and degradation. Hepatic Apg-2 expression promotes liver steatosis via AMPK signaling inhibition, suggesting that the regulation of Apg-2 activities is a therapeutic target for NAFLD.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

分子シャペロンが細胞死を迎えるべき細胞を救済するだけでなく、脂質や糖代謝に影響することで慢性炎症や発癌を助長していると考えられた。本来、いかに栄養を貯蓄し、効率よく使用することが生存に重要であった細胞にとって、近年の過栄養状態は想定されない状況と考えられる。この中で、分子シャペロンApg-2がLKB1の分解を通じてエネルギー貯蓄に重要であるという本研究の結果は、脂肪肝炎の病態解明に新たな知見となり得る。HSP70とHSP110の脂肪肝炎における個々の役割を明らかにすることで、慢性肝炎から肝硬変、肝がんへ至る長期的な病期に応じた治療法の開発に繋がると考えられた。