Inhibition of cholesterol and sphingolipid synthesis causes paradoxical effects on permeability barrier homeostasis.
Inhibition of cholesterol and sphingolipid synthesis causes paradoxical effects on permeability barrier homeostasis.
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胆固醇和鞘脂合成的抑制会对通透性屏障稳态产生矛盾的影响。
DOI：
10.1111/1523-1747.ep12363729
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Elias,PM
中科院分区：
文献类型：
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作者：
Mao-Qiang,M;Feingold,KR;Elias,PM
胆固醇、脂肪酸和鞘磷脂的合成是屏障稳态所必需的，研究表明，这些物种的合成在屏障修复的同时被刺激。此外，用两种限速酶HMGCoA还原酶(洛伐他汀、氟伐他汀)和丝氨酸棕榈酰转移酶(β-氯丙氨酸)的抑制剂阻断这些脂质的合成，改变了屏障修复的动力学。虽然这些研究显示了对这些脂类的单独需求，但我们在这里询问这些脂类是以添加的方式还是以合作的方式需要的。我们将每一类抑制剂单独应用于丙酮处理的皮肤，或将两类抑制剂一起应用于丙酮处理的皮肤，或将每一类单独应用于必需脂肪酸缺乏的小鼠皮肤。当氟伐他汀或β-氯丙氨酸单独应用于丙酮处理的皮肤时，每种药物分别导致屏障恢复的早期或晚期延迟(评估为经表皮水分丢失)。然而，当它们一起应用时，它们在早期没有造成进一步的恶化，而在后来的时间点却出现了矛盾的改善。这种改善与神经鞘氨酸脂的加速恢复有关，这可能是由于HMGCoA还原酶抑制剂诱导的脂质合成的整体刺激。在必需脂肪酸缺乏的动物中，抑制HMGCoA还原酶导致临床表现和屏障功能的急剧恶化，但β-氯丙氨酸引起矛盾的改善，这与表皮鞘磷脂的显著减少有关。这些结果与胆固醇和鞘脂对屏障稳态的要求是一致的，也与这两种脂必须存在(与游离脂肪酸一起)以实现最佳屏障功能的建议是一致的。
Cholesterol, fatty acid, and sphingolipid synthesis are required for barrier homeostasis, as demonstrated by studies where synthesis of these species is stimulated in parallel with barrier repair. Moreover, blockade of synthesis of these lipids with inhibitors of two of the rate-limiting enzymes, HMGCoA reductase (lovastatin, fluvastatin) and serine palmitoyl transferase (β-chloroalanine), alters the kinetics of barrier repair. Whereas these studies demonstrated a requirement for these lipids individually, we asked here whether these lipids are required in either an additive or cooperative fashion. We applied each class of inhibitor alone or the two classes of inhibitors together to acetone-treated skin, or each class separately to essential fatty acid deficient murine skin. When fluvastatin or β-chloroalanine was applied individually to acetone-treated skin, each caused a delay in the early or late stages of barrier recovery, respectively (assessed as trans-epidermal water loss). However, when applied together they caused no further worsening at the early time point and a paradoxical improvement at the later time points. This improvement correlated with an accelerated return of sphingo- lipids, which was perhaps due to a global stimulation of lipid synthesis induced by HMGCoA reductase inhibitors. In essential fatty acid deficient animals, inhibition of HMGCoA reductase caused drastic worsening of both clinical appearance and barrier function, but β-chloroalanine caused a paradoxical improvement, which correlated with a significant reduction in epidermal sphingolipids. These results are consistent with a requirement for both cholesterol and sphingolipids for barrier homeostasis, and also with the suggestion that both of these lipids must be present (with free fatty acids) for optimal barrier function.