Hashimoto F, Ishikawa T, Hamada S, Hayashi H
Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
Biochem Pharmacol. 1995 May 11;49(9):1213-21. doi: 10.1016/0006-2952(95)00041-w.
The effect of gemfibrozil, a peroxisome proliferator, on lipid biosynthesis from acetyl-CoA derived from peroxisomal beta-oxidation was studied. The specific activity of the peroxisomal fatty acyl-CoA beta-oxidation system of rats fed a chow containing 0.2% gemfibrozil for 2 weeks was approximately five times higher than that of control rats. When [1-14C]lignoceric acid, a very-long-chain fatty acid which is degraded exclusively by the peroxisomal beta-oxidation system at first, was injected into rats treated with gemfibrozil, radioactivity and content of bile acid in the bile were enhanced to approximately 2.2 and 3.5 times the control, respectively. Gemfibrozil increased the radioactivity and content of chenodeoxycholic acid more than that of cholic acid. The incorporation of radioactivity into cholesterol in the bile was as much as 4.5 times greater than the control, and content was 2.6 times greater. In the liver, incorporation of [14C]lignoceric acid into the simple lipids phosphatidylethanolamine and phosphatidylcholine was unaffected by gemfibrozil. The radioactivity and content of cholesterol separated from the simple lipids were also virtually unaffected. However, the specific activities of 3-hydroxy-3-methylglutararyl-CoA reductase (rate-limiting enzyme of cholesterol synthesis) of peroxisomes and microsomes were remarkably stimulated by gemfibrozil treatment. These results suggest that biosyntheses of cholesterol and bile acid from acetyl-CoA derived from peroxisomal beta-oxidation are stimulated by gemfibrozil, due at least in part to activation of the peroxisomal beta-oxidation system and 3-hydroxy-3-methylglutaryl-CoA reductase of peroxisomes and/or microsomes. Most peroxisomal proliferators (e.g. clofibrate) have been known to inhibit 3-hydroxy-3-methylglutaryl-CoA reductase activity. Therefore, gemfibrozil is expected to be a very useful tool for elucidating the relationship between peroxisomes and the biosyntheses of cholesterol and bile acid.
研究了过氧化物酶体增殖剂吉非贝齐对源自过氧化物酶体β-氧化的乙酰辅酶A的脂质生物合成的影响。给大鼠喂食含0.2%吉非贝齐的食物2周后，其过氧化物酶体脂肪酰辅酶Aβ-氧化系统的比活性比对照大鼠高约5倍。当将[1-¹⁴C]二十四烷酸（一种最初仅由过氧化物酶体β-氧化系统降解的极长链脂肪酸）注射到用吉非贝齐处理的大鼠体内时，胆汁中胆汁酸的放射性和含量分别增加到对照的约2.2倍和3.5倍。吉非贝齐使鹅去氧胆酸的放射性和含量增加得比胆酸更多。胆汁中胆固醇的放射性掺入量比对照高4.5倍，含量比对照高2.6倍。在肝脏中，[¹⁴C]二十四烷酸掺入简单脂质磷脂酰乙醇胺和磷脂酰胆碱不受吉非贝齐影响。从简单脂质中分离出的胆固醇的放射性和含量实际上也未受影响。然而，吉非贝齐处理显著刺激了过氧化物酶体和微粒体中3-羟基-3-甲基戊二酰辅酶A还原酶（胆固醇合成的限速酶）的比活性。这些结果表明，吉非贝齐刺激了源自过氧化物酶体β-氧化的乙酰辅酶A的胆固醇和胆汁酸生物合成，这至少部分归因于过氧化物酶体β-氧化系统以及过氧化物酶体和/或微粒体中3-羟基-3-甲基戊二酰辅酶A还原酶的激活。大多数过氧化物酶体增殖剂（如氯贝丁酯）已知会抑制3-羟基-3-甲基戊二酰辅酶A还原酶活性。因此，吉非贝齐有望成为阐明过氧化物酶体与胆固醇和胆汁酸生物合成之间关系的非常有用的工具。
