Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
J Eur Acad Dermatol Venereol. 2022 Aug;36(8):1325-1333. doi: 10.1111/jdv.18079. Epub 2022 Mar 24.
Minocycline is a second-generation tetracycline drug, which is widely used to treat diverse infectious and inflammatory diseases such as acne vulgaris. The effects of minocycline on acne vulgaris have been mainly attributed to its anti-inflammatory effect; however, its sebum-regulating effect and the relevance to epigenetic regulation in human sebaceous glands remain uninvestigated.
To identify the potential underlying epigenetic mechanism of sebum-inhibitory effects of minocycline in human SZ95 sebocytes.
The quantity of lipid droplets and the expression of key lipogenic genes were analysed in minocycline-treated SZ95 sebocytes. To examine whether the sebum-inhibitory effects of minocycline are relevant to histone acetylation, we analysed the effects of minocycline on p300 HAT and total HDAC activity. To elucidate the functional implication of p300 HAT inhibition by minocycline in sebocytes, we assessed the effect of p300 knockdown, inhibition and overexpression on lipid accumulation in SZ95 sebocytes.
Minocycline suppressed the insulin and liver X receptor agonist-induced lipid accumulation and the expression of the key lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) and its downstream genes, fatty acid synthase (FAS) and acetyl-CoA carboxylase α (ACCα). Minocycline inhibited p300 HAT activity in a concentration-dependent manner, but demonstrated no effect on global HDAC activity, resulting in a significant decrease in histone acetylation. Downregulation of p300 by knockdown or inhibition significantly suppressed SREBP1 expression, histone acetylation and lipid accumulation, whereas p300 overexpression enhanced these effects. Moreover, p300 overexpression rescued minocycline-inhibited SREBP1 expression and lipid synthesis.
Our findings revealed a novel sebum-regulating effect of minocycline. Moreover, as p300 HAT is a key epigenetic regulator of sebaceous lipogenesis, its inhibitors could be used for the treatment of acne vulgaris.
米诺环素是第二代四环素类药物，广泛用于治疗寻常痤疮等多种感染性和炎症性疾病。米诺环素治疗寻常痤疮的作用主要归因于其抗炎作用；然而，其皮脂调节作用及其与人类皮脂腺中表观遗传调控的相关性尚未得到研究。
在人类 SZ95 皮脂腺细胞中确定米诺环素抑制皮脂作用的潜在表观遗传机制。
分析米诺环素处理的 SZ95 皮脂腺细胞中的脂滴数量和关键脂肪生成基因的表达。为了研究米诺环素抑制皮脂作用是否与组蛋白乙酰化有关，我们分析了米诺环素对 p300 HAT 和总 HDAC 活性的影响。为了阐明米诺环素抑制皮脂腺中 p300 HAT 的功能意义，我们评估了 p300 敲低、抑制和过表达对 SZ95 皮脂腺细胞中脂质积累的影响。
米诺环素抑制胰岛素和肝 X 受体激动剂诱导的脂质积累以及关键脂肪生成转录因子固醇调节元件结合蛋白 1（SREBP1）及其下游基因脂肪酸合酶（FAS）和乙酰辅酶 A 羧化酶 α（ACCα）的表达。米诺环素呈浓度依赖性抑制 p300 HAT 活性，但对总 HDAC 活性无影响，导致组蛋白乙酰化显著降低。通过敲低或抑制下调 p300 显著抑制 SREBP1 表达、组蛋白乙酰化和脂质积累，而 p300 过表达增强了这些效应。此外，p300 过表达挽救了米诺环素抑制的 SREBP1 表达和脂质合成。
我们的研究结果揭示了米诺环素的一种新的皮脂调节作用。此外，由于 p300 HAT 是皮脂腺脂肪生成的关键表观遗传调节剂，其抑制剂可用于治疗寻常痤疮。
