New therapeutic strategy for NASH-related HCC targeting lipid metabolism
| Project/Area Number |
15K19313
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2015-04-01 – 2018-03-31
|
| Project Status |
Completed (Fiscal Year 2017)
|
| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | NASH / 肝細胞癌 / メタボリックリプログラミング / CPT2 / アシルカルニチン / 脂質代謝リプログラミング / 肝癌 / 脂肪酸合成 / メタボローム |
|---|
| Outline of Final Research Achievements |
We conducted untargeted metabolomics profiling using obesity-driven HCC mouse models, and found suppression of fatty acid β-oxidation (FAO) and subsequent extensive accumulation of acylcarnitine species in HCC tissues, which was caused by downregulation of CPT2, a key enzyme of FAO. CPT2 downregulation enabled HCC cells to escape lipotoxicity by inhibiting Src-mediated JNK activation, and accumulated acylcarnitine, specifically oleoylcarnitine, enhanced carcinogenesis by conferring stem cell properties to HCC through STAT3 activation. A high-fat diet and carnitine supplementation synergistically promoted HCC development with acylcarnitine accumulation in mice. Intriguingly, in obesity-driven HCC, glucose was utilized for oxidative phosphorylation to compensate suppressed FAO, unlike the Warburg effect. NASH-HCC patients also revealed CPT2-mediated metabolic reprogramming. Increased serum acylcarnitine was a potential biomarker of NASH-HCC.
|
Report
(4 results)
Research Products
(10 results)
-
-
[Journal Article] p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells2016
Author(s)
Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M
-
Journal Title
Cancer Cell
Volume: 29
Issue: 6
Pages: 935-948
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
[Journal Article] Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.2015
Author(s)
6.Font-Burgada J, Shalapour S, Ramaswamy S, Hsueh B, Rossell D, Umemura A, Taniguchi K, Nakagawa H, Valasek MA, Ye L, Kopp JL, Sander M, Carter H, Deisseroth K, Verma IM, Karin M.
-
Journal Title
Cell
Volume: 162
Issue: 4
Pages: 766-79
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
-
-
-
-
