Project/Area Number |
08671146
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
内分泌・代謝学
|
Research Institution | Hamamatsu University School of Medicline |
Principal Investigator |
GOTO Yoshinori Hamamatsu University School of Medicline, Assistant, 医学部, 助手 (60252178)
|
Project Period (FY) |
1996 – 1998
|
Project Status |
Completed (Fiscal Year 1998)
|
Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥1,400,000 (Direct Cost: ¥1,400,000)
|
Keywords | retinoic acid / hypertriglyceridemia / lipogenesis / fatty acid synthase / malic enzyme / S14 / PPAR γ |
Research Abstract |
Recent progress in differentiation-induction treatment of acute promyelocytic leukemia by all-trans- retinoic acid (ATRA) is remarkable that complete remission rate has reached 60%. However hypertriglyceridemia has been frequently found as the adverse effect of ATRA.We postulate that hypertriglyceridemia caused by ATRA is due to increased synthesis of triglyceride. To elucidate this hypothesis the effects of ATRA on serum lipids and activity of fatty acid synthase (FAS) and malic enzyme (ME) which are key enzymes in lipogenesis in liver, white (WAT) and brown adipose tissues (BAT) were investigated in rats. ATRA (0.1-1 mg/100gBW) administered through either intraperitoneal injection or oral gavage increased serum triglyceride concentration in dose-dependent manner. This result was consistent with the human study. In WAT FAS activity was increased proportionally to the ATRA dose. There was a tendency that FAS activity in liver and BAT was increased by ATRA in dose-dependent manner. This is the first report demonstrating that ATRA upregulates the lipogenic key enzymes, FAS and ME.Peroxisome proliferator-activated receptor (PPAR) gamma is the important regulator of the adipose tissue differentiation and the insulin resistance. Injection of troglitazone, the ligand for PPARgamma, alone had no effect on serum triglyceride and cholesterol concentration, and the activity of ME and FAS in liver, WAT and BAT.However when troglitazone and ATRA were coinjected, the increase of serum triglyceride concentration induced by ATRA was suppressed by troglitazone in dose-dependent manner and there was a tendency that troglitazone inhibited the increase of FAS activity induced by ATRA in liver. This study will contribute to the establishment of the prevention of hypertriglyceridemia induced by ATRA and to elucidate the mechanisms of the regulation of lipid metabolism by retinoic acid.
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