Elucidation of mechanism on hepatitis C-related liver cancer exacerbation by trans-fatty acid toxicity and development of preventive method

• Project/Area Number: 16K08616
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Shinshu University
• Principal Investigator: AOYAMA Toshifumi 信州大学, 学術研究院医学系, 教授 (50231105)
• Co-Investigator(Kenkyū-buntansha): 田中 直樹 信州大学, 学術研究院医学系, 准教授 (80419374)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HCV / トランス脂肪酸 / 肝がん / C型肝炎ウイルスコア蛋白 / PPARalpha / デオキシコール酸 / トランス脂肪酸食 / 肝臓非癌部・癌部 / スルファチド / 脂質 / 発癌 / C型肝炎

Outline of Final Research Achievements

Transgenic mice expressing the hepatitis C virus core protein develop liver cancer at a frequency of about 30-35% at around 18 months of age. We fed 12-13-month-old male transgenic mice with a diet containing trans-fatty acids for 5 months and found liver tumors in all of these mice, demonstrating the strong liver tumorigenic effect of trans-fatty acids. These transgenic mice fed a trans-fatty acid-rich diet also showed marked hepatic steatosis, inflammation, and fibrosis in their non-tumorous liver tissues, which accompanied with activated inflammatory signaling, increased oxidative and endoplasmic reticulum stress, and accelerated cell proliferation. These changes likely contributed to promotion of liver tumorigenesis by trans-fatty acid-rich diet.

Academic Significance and Societal Importance of the Research Achievements

多くの加工食品に含まれるトランス脂肪酸は、健常人に対して、LDLコレステロールの増加に伴う心血管疾患のリスクを増加させ、また、肥満・アレルギー性疾患・認知症等を誘発する毒性を示すことが知られている。しかし、肝発癌に与える影響は明らかにされていない。本研究から、トランス脂肪酸がHCV関連肝癌の発症リスクを高める可能性が初めて示唆された。HCV持続感染者ではトランス脂肪酸の摂取量を制限することが肝発癌抑制に有効である可能性が期待される。

Research Products

• [Journal Article] A high-cholesterol diet promotes steatohepatitis and liver tumorigenesis in HCV core gene transgenic mice. (2019)
  • Author(s): Wang X, Tanaka N, Hu X, Kimura T, Lu Y, Jia F, Sato Y, Nakayama J, Moriya K, Koike K, Aoyama T
  • Journal Title: Arch Toxicol. Volume: in press Issue: 6 Pages: 1713-1725
  • DOI: 10.1007/s00204-019-02440-7
  • Peer Reviewed
• [Journal Article] Age-dependent PPARα activation induces hepatic sulfatide accumulation in transgenic mice carrying the hepatitis C virus core gene. (2016)
  • Author(s): Tian Y, Yang Y, Zhang X, Nakajima T, Tanaka N, Sugiyama E, Kamijo Y, Lu Y, Moriya K, Koike K, Gonzalez FJ, Aoyama T.
  • Journal Title: Glycoconj J Volume: 33 Issue: 6 Pages: 927-936
  • DOI: 10.1007/s10719-016-9703-1
  • Peer Reviewed / Open Access / Int'l Joint Research