Mao-Qiang M, Feingold K R, Elias P M
Dermatology Service, Veterans Administration Medical Center, San Francisco, CA 94121.
J Invest Dermatol. 1993 Aug;101(2):185-90. doi: 10.1111/1523-1747.ep12363729.
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 (beta-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 beta-chloroalanine was applied individually to acetone-treated skin, each caused a delay in the early or late stages of barrier recovery, respectively (assessed as transepidermal 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 sphingolipids, 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 beta-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.
胆固醇、脂肪酸和鞘脂的合成对于屏障稳态是必需的，这一点已在相关研究中得到证实，这些研究表明这些物质的合成与屏障修复同时受到刺激。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，会改变屏障修复的动力学。虽然这些研究分别证明了对这些脂质的需求，但我们在此询问这些脂质是以相加还是协同的方式被需要。我们将每一类抑制剂单独应用，或将两类抑制剂一起应用于丙酮处理过的皮肤，或者将每一类抑制剂分别应用于必需脂肪酸缺乏的小鼠皮肤。当单独将氟伐他汀或β-氯丙氨酸应用于丙酮处理过的皮肤时，它们分别导致屏障恢复的早期或晚期延迟（以经表皮水分流失来评估）。然而，当一起应用时，它们在早期时间点并未导致进一步恶化，反而在后期时间点出现了矛盾的改善。这种改善与鞘脂的加速恢复相关，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还原酶会导致临床外观和屏障功能急剧恶化，但β-氯丙氨酸却导致了矛盾的改善，这与表皮鞘脂的显著减少相关。这些结果与屏障稳态需要胆固醇和鞘脂一致，也与这两种脂质（与游离脂肪酸一起）必须存在才能实现最佳屏障功能的观点一致。
