Basic Research and Innovation Division, Bioscience Laboratory, AmorePacific Corporation R&D Center, Yongin-si, Gyeonggi-do, South Korea.
Exp Mol Med. 2020 Feb;52(2):293-307. doi: 10.1038/s12276-020-0388-y. Epub 2020 Feb 21.
Lipin-1 is an Mg-dependent phosphatidate phosphatase (PAP1) that catalyzes a critical step in the synthesis of glycerophospholipids and is also a cotranscriptional regulator. The role of lipin-1 in the regulation of inflammatory responses has been extensively studied in various cell types but not in skin cells. In the present study, the function of lipin-1 in UVB-induced proinflammatory responses was assessed in normal human epidermal keratinocytes (NHEKs). UVB radiation downregulated lipin-1 expression. Lipin-1 inhibition was mediated by UVB-dependent sterol-response element binding protein-1 (SREBP-1) inhibition. The UVB-dependent inhibition of lipin-1 and SREBP-1 was mediated by AMPK activation. UVB-induced activation of JNK was dependent on AMPK activation and mediated lipin-1 inhibition. Prevention of UVB-mediated lipin-1 repression by introducing a lipin-1 expression vector stimulated IL-6 and IL-8 production, suggesting that lipin-1 inhibition attenuates UVB-induced IL-6 and IL-8 production. The downregulation of lipin-1 ameliorated UVB-induced NF-ĸB phosphorylation, which might be attributed to the suppression of UVB-induced accumulation of free fatty acids (FFAs). Pharmacological inhibition of PAP1 with propranolol suppressed UVB-induced production of IL-6 and IL-8 in NHEKs and reconstituted human skin models. Taken together, lipin-1 is downregulated by exposure to UVB radiation, which confers protection against UVB-induced proinflammatory responses; therefore, the inhibition of lipin-1 is a potential strategy for photoaging.
脂联素-1 是一种依赖镁的磷酸脂酶（PAP1），可催化甘油磷脂合成的关键步骤，也是一种共转录调节因子。脂联素-1 在各种细胞类型的炎症反应调节中的作用已被广泛研究，但在皮肤细胞中尚未研究。在本研究中，在正常的人表皮角质形成细胞（NHEK）中评估了脂联素-1 在 UVB 诱导的促炎反应中的作用。UVB 辐射下调了脂联素-1 的表达。脂联素-1 的抑制是通过 UVB 依赖性固醇反应元件结合蛋白-1（SREBP-1）的抑制介导的。UVB 依赖性的脂联素-1 和 SREBP-1 的抑制是通过 AMPK 的激活介导的。UVB 诱导的 JNK 激活依赖于 AMPK 的激活，并介导脂联素-1 的抑制。通过引入脂联素-1 表达载体来预防 UVB 介导的脂联素-1 抑制，可刺激 IL-6 和 IL-8 的产生，表明脂联素-1 的抑制减弱了 UVB 诱导的 IL-6 和 IL-8 的产生。脂联素-1 的下调改善了 UVB 诱导的 NF-ĸB 磷酸化，这可能归因于抑制了 UVB 诱导的游离脂肪酸（FFAs）的积累。用普萘洛尔抑制 PAP1 的药理学抑制作用抑制了 NHEK 和重建的人体皮肤模型中 UVB 诱导的 IL-6 和 IL-8 的产生。总之，脂联素-1 被 UVB 辐射下调，这赋予了对 UVB 诱导的促炎反应的保护作用；因此，脂联素-1 的抑制可能是光老化的一种潜在策略。
