Study on the mechanism of free cholesterol metabolism of hepatic stellate cell in liver fibrosis

• Project/Area Number: 24790719
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: TERATANI TOSHIAKI 慶應義塾大学, 医学部, 助教 (40624408)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 遊離コレステロール / 肝臓線維化 / Free cholesterol / 非アルコール性脂肪肝炎 / 肝臓 / 線維化 / コレステロール

Outline of Final Research Achievements

Given the growing number of metabolic syndrome patients in recent years, the incidence of nonalcoholic steatohepatitis increases in Japan. Accumulation of free cholesterol in hepatic stellate cell (HSC) increased levels of Toll-like receptor 4 (TLR4), leading to down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor (a pseudoreceptor for transforming growth factor [TGF]β); the HSCs became sensitized to TGFβ-induced activation. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol to cholesterol ester, which prevents excess accumulation of free cholesterol. ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced free cholesterol accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.

Research Products

• [Journal Article] Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. (2014)
  • Author(s): Teratani T (28人中2番目), et al.
  • Journal Title: J Hepatol. Volume: 61 Pages: 98-106
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice (2014)
  • Author(s): Tomita, K. Teratani, T. Suzuki, T. Shimizu, M. Sato, H. Narimatsu, K. Okada, Y. Kurihara, C. Irie, R. Yokoyama, H. Shimamura, K. Usui, S. Ebinuma, H. Saito, H. Watanabe, C. Komoto, S. Kawaguchi, A. Nagao, S. Sugiyama, K. Hokari, R. Kanai, T. Miura, S. Hibi, T.
  • Journal Title: Hepatology Volume: 59 Issue: 1 Pages: 154-169
  • DOI: 10.1002/hep.26604
  • Peer Reviewed
• [Journal Article] Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. (2014)
  • Author(s): Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Usui S, Furuhashi H, Kimura A, Nishiyama K, Maejima T, Okada Y, Kurihara C, Shimamura K, Ebinuma H, Saito H, Yokoyama H, Watanabe C, Komoto S, Nagao S, Sugiyama K, Aosasa S, Hatsuse K, Yamamoto J, Hibi T, Miura S, Hokari R, Kanai T.
  • Journal Title: Journal of Hepatology Volume: 印刷中 Issue: 1 Pages: 98-106
  • DOI: 10.1016/j.jhep.2014.03.018
  • Peer Reviewed
• [Journal Article] p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. (2012)
  • Author(s): Tomita K, Teratani T, Shimamura K, Nishiyama N, Mataki R, Irie T, Minamino Y, Okada C, Kurihara H, Sugiyama K, et al
  • Journal Title: J Hepatol Volume: 57 Issue: 4 Pages: 837-843
  • DOI: 10.1016/j.jhep.2012.05.013
  • Peer Reviewed
• [Presentation] 高コレステロール食摂取は、肝臓類洞内皮細胞のTLR9シグナル増強を介してアセトアミノフェンによる肝障害を増悪させる。
  • Author(s): 寺谷俊昭
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸