Musanti R, Giorgini L, Lovisolo P P, Pirillo A, Chiari A, Ghiselli G
Pharmacia Farmitalia Carlo Erba Research Institute, Cardiovascular Department, Milan, Italy.
J Lipid Res. 1996 Jan;37(1):1-14.
There is evidence that the overproduction of apoB-100-containing lipoproteins by the liver is the underlying event in some forms of dyslipoproteinemia. This metabolic status is associated to an increased risk of developing premature coronary artery disease CAD. The conclusions from previous studies suggested that the availability to the hepatocytes of cholesterol that is readily esterified is an important determinant for VLDL and LDL secretion. In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100 secretion rate from a human hepatoma cell line (HepG2). When the specific ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of the cellular cholesteryl ester content and at the same time a significant reduction of the neutral lipids and of the apoB-100 secretion rate were noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml) caused a 4-fold increase of the cellular cholesteryl ester content and a 2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to 10-7 M) prevented the effects elicited by the oxysterol. On the contrary, lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of the lipid and of the apolipoprotein composition of the lipoproteins secreted in the medium revealed that ACAT inhibition had the dual effect of both decreasing the number of apoB-100-containing lipoproteins secreted as well as their cholesteryl ester load. Altogether, these data support the idea of a close relationship between ACAT activation, leading to increased cholesteryl ester availability, and apoB-100-containing lipoprotein secretion. It is speculated that ACAT inhibitors may prove useful for the treatment of human dyslipoproteinemias caused by the hepatic overproduction of apoB-100-containing lipoproteins.
有证据表明，肝脏中含载脂蛋白B-100的脂蛋白产生过多是某些形式的血脂蛋白异常血症的潜在病因。这种代谢状态与过早发生冠状动脉疾病（CAD）的风险增加相关。先前研究的结论表明，易于酯化的胆固醇对肝细胞的可用性是极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）分泌的重要决定因素。在本研究中，我们着手研究胆固醇酯化限速酶酰基辅酶A：胆固醇酰基转移酶（ACAT，E.C. 2.3.1.26）的特异性刺激和抑制对人肝癌细胞系（HepG2）脂质和载脂蛋白B-100分泌率的影响。当向培养物中加入特异性ACAT抑制剂FCE 27677（10-5 M）时，细胞胆固醇酯含量降低，同时中性脂质和载脂蛋白B-100分泌率显著降低。25-羟基胆固醇（20微克/毫升）刺激ACAT导致细胞胆固醇酯含量增加4倍，脂蛋白分泌率增加2倍。FCE 27677（10-5 M至10-7 M）可阻止氧甾醇引发的效应。相反，洛伐他汀（10-6 M）和吉非贝齐（10-6 M）没有效果。对培养基中分泌的脂蛋白的脂质和载脂蛋白组成分析表明，ACAT抑制具有双重作用，既减少了含载脂蛋白B-100的脂蛋白的分泌数量，也降低了它们的胆固醇酯含量。总之，这些数据支持了ACAT激活导致胆固醇酯可用性增加与含载脂蛋白B-100的脂蛋白分泌之间密切关系的观点。据推测，ACAT抑制剂可能被证明对治疗由肝脏中含载脂蛋白B-100的脂蛋白产生过多引起的人类血脂蛋白异常血症有用。
