Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Front Endocrinol (Lausanne). 2021 Feb 26;12:624112. doi: 10.3389/fendo.2021.624112. eCollection 2021.
The proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is one of the most extensively studied ligand-inducible transcription factors. Since its identification in the early 1990s, PPARγ is best known for its critical role in adipocyte differentiation, maintenance, and function. Emerging evidence indicates that PPARγ is also important for the maturation and function of various immune system-related cell types, such as monocytes/macrophages, dendritic cells, and lymphocytes. Furthermore, PPARγ controls cell proliferation in various other tissues and organs, including colon, breast, prostate, and bladder, and dysregulation of PPARγ signaling is linked to tumor development in these organs. Recent studies have shed new light on PPARγ (dys)function in these three biological settings, showing unified and diverse mechanisms of action. Classical transactivation-where PPARγ activates genes upon binding to PPAR response elements as a heterodimer with RXRα-is important in all three settings, as underscored by natural loss-of-function mutations in FPLD3 and loss- and gain-of-function mutations in tumors. Transrepression-where PPARγ alters gene expression independent of DNA binding-is particularly relevant in immune cells. Interestingly, gene translocations resulting in fusion of PPARγ with other gene products, which are unique to specific carcinomas, present a third mode of action, as they potentially alter PPARγ's target gene profile. Improved understanding of the molecular mechanism underlying PPARγ activity in the complex regulatory networks in metabolism, cancer, and inflammation may help to define novel potential therapeutic strategies for prevention and treatment of obesity, diabetes, or cancer.
过氧化物酶体增殖物激活受体 γ（PPARγ）是核受体超家族的成员之一，是研究最为广泛的配体诱导转录因子之一。自 20 世纪 90 年代初被发现以来，PPARγ 最为人所知的是其在脂肪细胞分化、维持和功能中的关键作用。新出现的证据表明，PPARγ 对于各种与免疫系统相关的细胞类型的成熟和功能也很重要，例如单核细胞/巨噬细胞、树突状细胞和淋巴细胞。此外，PPARγ 还控制着包括结肠、乳腺、前列腺和膀胱在内的各种其他组织和器官中的细胞增殖，PPARγ 信号通路的失调与这些器官中的肿瘤发展有关。最近的研究在这三个生物学背景下揭示了 PPARγ（异常）功能，展示了统一而多样化的作用机制。经典的反式激活——PPARγ 在与 RXRα 形成异二聚体结合 PPAR 反应元件后激活基因——在所有三个背景下都很重要，正如 FPLD3 中的自然功能丧失突变和肿瘤中的功能丧失和获得性突变所强调的那样。反式阻遏——PPARγ 独立于 DNA 结合改变基因表达——在免疫细胞中尤为相关。有趣的是，导致 PPARγ 与其他基因产物融合的基因易位，这些融合仅存在于特定的癌中，呈现出第三种作用机制，因为它们可能改变 PPARγ 的靶基因谱。对 PPARγ 在代谢、癌症和炎症复杂调控网络中的活性的分子机制的深入了解，可能有助于定义预防和治疗肥胖、糖尿病或癌症的新的潜在治疗策略。
