Abstract:
The aryl hydrocarbon receptor (AHR) mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity that can lead to chloracne in humans. A characteristic of chloracne, in contrast to acne vulgaris, is shrinkage or loss of sebaceous glands. Acne vulgaris, on the other hand, is often accompanied by excessive sebum production. Here, we examined the role of AHR in lipid synthesis in human sebocytes using distinct classes of AHR ligands. Modulation of AHR activity attenuated the expression of lipogenic genes and key proinflammatory markers in the absence of canonical DRE-driven transcription of the AHR target gene CYP1A1. Furthermore, topical treatment with TCDD, which mediates DRE-dependent activity, and SGA360, which fails to induce DRE-mediated responses, both exhibited a decrease in the size of sebaceous glands and the number of sebocytes within each gland in the skin. To elucidate the mechanism of AHR-mediated repression of lipid synthesis, we demonstrated that selective AHR modulators, SGA360 and SGA315 increased the protein turnover of the mature sterol regulatory element-binding protein (mSREBP-1), the principal transcriptional regulator of the fatty acid synthesis pathway. Interestingly, selective AHR ligand treatment significantly activated the AMPK-dependent kinase (AMPK) in sebocytes. Moreover, we demonstrated an inverse correlation between the active AMPK and the mSREBP-1 protein, which is consistent with the previously reported role of AMPK in inhibiting cleavage of SREBP-1. Overall, our findings indicate a DRE-independent function of selective AHR ligands in modulating lipid synthesis in human sebocytes, which might raise the possibility of using AHR as a therapeutic target for treatment of acne.
摘要:
芳基烃受体(AHR)介导2,3,7,8-四氯二苯并-对二恶英(TCDD)诱导的毒性,可导致人类的氯痤疮。氯痤疮的特征,与寻常痤疮相比,是皮脂腺的收缩或损失。寻常痤疮,另一方面,通常伴随着过度的皮脂生产。这里,我们使用不同类别的AHR配体研究了AHR在人类皮脂腺细胞脂质合成中的作用。在缺乏典型DRE驱动的AHR靶基因CYP1A1转录的情况下,AHR活性的调节减弱了脂肪生成基因和关键促炎标志物的表达。此外,TCDD局部治疗,介导DRE依赖性活动,和SGA360,它不能诱导DRE介导的反应,两者均显示皮脂腺的大小和皮肤中每个腺体中皮脂腺的数量减少。为了阐明AHR介导的脂质合成抑制的机制,我们证明了选择性AHR调节剂,SGA360和SGA315增加了成熟固醇调节元件结合蛋白(mSREBP-1)的蛋白质周转,脂肪酸合成途径的主要转录调节因子。有趣的是,选择性AHR配体处理显著激活皮脂腺细胞中的AMPK依赖性激酶(AMPK)。此外,我们证明了活性AMPK和mSREBP-1蛋白之间的负相关,这与先前报道的AMPK在抑制SREBP-1裂解中的作用一致。总的来说,我们的发现表明,选择性AHR配体在调节人类皮脂腺细胞的脂质合成中具有不依赖DRE的功能,这可能会提高使用AHR作为治疗痤疮的治疗靶点的可能性。