Man Mao-Qiang, Choi Eung-Ho, Schmuth Matt, Crumrine Debra, Uchida Yoshikazu, Elias Peter M, Holleran Walter M, Feingold Kenneth R
Department of Dermatology, University of California and VA Medical Center, San Francisco, California 94121, USA.
J Invest Dermatol. 2006 Feb;126(2):386-92. doi: 10.1038/sj.jid.5700046.
Previously, we demonstrated that topical applications of peroxisome proliferator-activated receptors (PPARs) and liver X receptor (LXR) activators improve permeability barrier homeostasis. We showed further that stimulation of epidermal differentiation provides one mechanism that could account for such improvement. Here, we studied the effects of these agents on the lipid matrix of the stratum corneum. Hairless mice were treated topically with activators of PPARalpha (WY14643), PPARdelta (GW1514), PPARgamma (ciglitazone), and LXR (22(R)-cholesterol or TO901317) or vehicle twice daily for 3 days. All activators significantly increased epidermal cholesterol, fatty acid, and sphingolipid synthesis, including the production of barrier-specific ceramide species. In addition, lamellar body (LB) formation, secretion, and post-secretory processing accelerated significantly following acute barrier disruption in PPAR/LXR-activator-treated animals. Finally, the activity of epidermal beta-glucocerebrosidase, a key lipid-processing enzyme, increased in PPAR/LXR-activator-treated animals. Thus, topical PPAR and LXR activators stimulate epidermal lipid synthesis, increase LB secretion, and accelerate extracellular lipid processing, providing additional mechanisms that further account for their ability to improve epidermal permeability barrier homeostasis. Since the liposensors are activated by endogenous lipid metabolites, they may serve as unique regulators of barrier homeostasis.
此前，我们证明过，过氧化物酶体增殖物激活受体（PPARs）和肝X受体（LXR）激活剂的局部应用可改善通透性屏障的稳态。我们还进一步表明，刺激表皮分化是可以解释这种改善的一种机制。在此，我们研究了这些药物对角质层脂质基质的影响。将无毛小鼠每日两次局部给予PPARα激活剂（WY14643）、PPARδ激活剂（GW1514）、PPARγ激活剂（吡格列酮）和LXR激活剂（22(R)-胆固醇或TO901317）或赋形剂，持续3天。所有激活剂均显著增加表皮胆固醇、脂肪酸和鞘脂的合成，包括屏障特异性神经酰胺种类的产生。此外，在PPAR/LXR激活剂处理的动物中，急性屏障破坏后板层小体（LB）的形成、分泌和分泌后加工显著加速。最后，在PPAR/LXR激活剂处理的动物中，表皮β-葡萄糖脑苷脂酶（一种关键的脂质加工酶）的活性增加。因此，局部应用PPAR和LXR激活剂可刺激表皮脂质合成、增加LB分泌并加速细胞外脂质加工，这为它们改善表皮通透性屏障稳态的能力提供了更多机制。由于脂质传感器可被内源性脂质代谢物激活，它们可能是屏障稳态的独特调节因子。
