HMG-CoA reductase inhibitors perturb fatty acid metabolism and induce peroxisomes in keratinocytes.
HMG-CoA reductase inhibitors perturb fatty acid metabolism and induce peroxisomes in keratinocytes.
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发表时间：
1992-02
影响因子：
6.5
通讯作者：
M. Williams;G. Menon;K. Hanley
中科院分区：
文献类型：
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作者：
M. Williams;G. Menon;K. Hanley
局部洛伐他汀刺激表皮脂肪酸的合成在体内，因此，进行研究，以检查HMG-CoA还原酶抑制剂对培养的角质形成细胞中的脂肪酸代谢的影响。当暴露于氟吲哚司他丁或洛伐他汀大于或等于24小时，角质形成细胞在无血清培养基中积累尼罗红荧光脂滴。到72小时，三酰甘油和磷脂含量分别增加2.5倍和1.3倍。还原酶抑制剂（1-10 μ M）增加脂肪酸合成约1.5倍，增加合成后，注意到只有超过15小时的曝光，并分布在磷脂和三酰甘油。[14 C]棕榈酸酯氧化为CO2减少大于50%，在乙醇处理的文化，和标签积累在三酰甘油。抑制剂处理的角质形成细胞表现出过氧化物酶体的数量增加，使用二氨基联苯胺ultracycytochemistry。过氧化物酶体增生还表现为过氧化氢酶活性增加（1.5- 2.5倍），磷酸二羟丙酮酰基转移酶活性增加（1.4倍）和过氧化物酶体（KCN不敏感）脂肪酸氧化增加（1.4倍）在大肠杆菌处理的培养物。因此，HMG-CoA还原酶抑制剂增加脂肪酸合成，诱导三酰二醇和磷脂积累，并诱导培养的角质形成细胞中的过氧化物酶体。与低密度脂蛋白或25-羟基胆固醇共孵育防止过氧化物酶体增生和脂肪酸合成增加，这表明还原酶抑制剂的这些作用可能与其对胆固醇生物合成途径的影响有关。
Topical lovastatin stimulates epidermal fatty acid synthesis in vivo; therefore, studies were undertaken to examine the effects of HMG-CoA reductase inhibitors on fatty acid metabolism in cultured keratinocytes. When exposed to fluindostatin or lovastatin for greater than or equal to 24 h, keratinocytes in serum-free media accumulated nile red-fluorescent lipid droplets. By 72 h, the triacylglycerol and phospholipid content were increased 2.5- and 1.3-fold, respectively. Reductase inhibitors (1-10 microM) increased fatty acid synthesis approximately 1.5-fold; increased synthesis was noted only after greater than 15 h exposure and was distributed among phospholipids and triacylglycerols. Oxidation of [14C]palmitate to CO2 was decreased greater than 50% in inhibitor-treated cultures, and label accumulated in triacylglycerols. Inhibitor-treated keratinocytes exhibited increased numbers of peroxisomes, using diaminobenzidene ultracytochemistry. Peroxisomal hyperplasia was also demonstrated by increased catalase activity (1.5- to 2.5-fold), increased dihydroxyacetone phosphate acyltransferase activity (1.4-fold) and increased peroxisomal (KCN-insensitive) fatty acid oxidation (1.4-fold) in inhibitor-treated cultures. Thus HMG-CoA reductase inhibitors increase fatty acid synthesis, induce triacylglycol and phospholipid accumulation, and induce peroxisomes in cultured keratinocytes. Coincubations with either low density lipoproteins or 25-hydroxycholesterol prevented both the peroxisomal hyperplasia and increased fatty acid synthesis, suggesting that these effects of reductase inhibitors may be linked to their effects on the cholesterol biosynthetic pathway.