Mastrofrancesco A, Ottaviani M, Cardinali G, Flori E, Briganti S, Ludovici M, Zouboulis C C, Lora V, Camera E, Picardo M
Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy.
Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Thedore Fontane Medical University of Brandenburg, Dessau, Germany.
Biochem Pharmacol. 2017 Aug 15;138:96-106. doi: 10.1016/j.bcp.2017.04.030. Epub 2017 Apr 29.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.
核受体过氧化物酶体增殖物激活受体γ（PPARγ）控制参与脂质和葡萄糖代谢、细胞增殖/分化以及炎症途径调节的基因表达。在人类皮脂腺细胞和分离的皮脂腺中进行的关键研究提出了一种有趣的可能性，即作用于PPARγ的化合物可以调节皮脂和炎症，因此可能对痤疮治疗有用。为了研究该受体在脂质合成、增殖和炎症调节中的作用，我们使用了胰岛素刺激的SZ95皮脂腺细胞系。在皮脂腺细胞中，胰岛素信号激活磷脂酰肌醇3激酶-蛋白激酶B（PI3K/Akt）和雷帕霉素哺乳动物靶蛋白（mTOR）途径，进而诱导高蛋白/脂质合成、增加细胞生长和增殖以及炎症。关于脂肪生成，胰岛素最初刺激不饱和脂质的形成，然后刺激脂质的重新合成。结果表明，PPARγ的调节抵消了胰岛素诱导的脂肪生成改变，这通过负责脂肪酸合成的关键酶基因表达的降低以及通过油红O/尼罗红染色和气相色谱-质谱分析的脂质种类合成的减少而明显体现。PPARγ调节还调节胰岛素诱导的增殖，抑制细胞周期进程和p21WAF1/CIP1（p21）蛋白减少。此外，胰岛素或脂多糖（LPS）诱导的炎性细胞因子的表达被下调。在PPARγ缺陷细胞或存在GW9662拮抗剂的情况下，所有这些观察到的效应均被消除，表明PPARγ激活在调节脂肪生成、细胞增殖和炎症信号改变中起作用。我们证明，PPARγ活性的选择性调节可能代表一种治疗痤疮的策略。
