Leukotriene C4 synthase is a novel PPARγ target gene, and leukotriene C4 and D4 activate adipogenesis through cysteinyl LT1 receptors in adipocytes
Leukotriene C4 synthase is a novel PPARγ target gene, and leukotriene C4 and D4 activate adipogenesis through cysteinyl LT1 receptors in adipocytes
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DOI：
10.1016/j.bbamcr.2021.119203
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发表时间：
2022-03-01
影响因子：
5.1
通讯作者：
Maehara, Toko
中科院分区：
文献类型：
--
作者：
Fujimori, Ko;Uno, Saki;Maehara, Toko
白三烯（LT）C-4合酶（LTC 4S）催化LTA（4）转化为LTC 4，LTC 4是哮喘和其他炎性疾病中的促炎脂质介质。LTC 4被代谢为LTD 4和LTE 4，所有这些都被称为半胱氨酰（Cys）LT，并通过CysLT受体发挥生理功能。LTC 4S在脂肪细胞中表达。然而，CysLTs在脂肪细胞中的功能和调节机制仍不清楚。在这项研究中，我们研究了小鼠脂肪细胞3 T3-L1细胞中LTC 4S的表达和CysLTs的产生及其潜在的调控机制。在脂肪形成过程中，LTC 4S的表达以及LTC 4和CysLTs的产生增加，而siRNA介导的LTC 4S表达抑制通过减少脂肪形成基因的表达来抑制脂肪形成。CysLT 1受体是两种LTC 4受体之一，在脂肪细胞中表达。LTC 4和LTD 4增加了细胞内甘油三酯水平和脂肪形成基因表达，并且它们的增强被CysLT 1受体拮抗剂普仑司特共同治疗所抑制。此外，在脂肪形成过程中LTC 4S基因/蛋白的表达谱类似于过氧化物酶体增殖物激活受体（PPAR）γ。LTC 4S的表达进一步上调治疗与曲格列酮，过氧化物酶体增殖物激活受体γ激动剂。启动子荧光素酶和染色质免疫沉淀试验表明，在脂肪细胞中，PPAR γ直接结合到LTC 4S基因启动子的PPAR反应元件上。这些结果表明，LTC 4S基因表达被PPAR γ增强，LTC 4和LTD 4通过CysLT 1受体在3 T3-L1细胞中激活脂肪形成。因此，LTC 4S和CysLT 1受体是治疗肥胖症的新的潜在靶点。
Leukotriene (LT) C-4 synthase (LTC4S) catalyzes the conversion from LTA(4) to LTC4, which is a proinflammatory lipid mediator in asthma and other inflammatory diseases. LTC4 is metabolized to LTD4 and LTE4, all of which are known as cysteinyl (Cys) LTs and exert physiological functions through CysLT receptors. LTC4S is expressed in adipocytes. However, the function of CysLTs and the regulatory mechanism in adipocytes remain unclear. In this study, we investigated the expression of LTC4S and production of CysLTs in murine adipocyte 3T3-L1 cells and their underlying regulatory mechanisms. Expression of LTC4S and production of LTC4 and CysLTs increased during adipogenesis, whereas siRNA-mediated suppression of LTC4S expression repressed adipogenesis by reducing adipogenic gene expression. The CysLT1 receptor, one of the two LTC4 receptors, was expressed in adipocytes. LTC4 and LTD4 increased the intracellular triglyceride levels and adipogenic gene expression, and their enhancement was suppressed by co-treatment with pranlukast, a CysLT1 receptor antagonist. Moreover, the expression profiles of LTC4S gene/protein during adipogenesis resembled those of peroxisome proliferator-activated receptor (PPAR) gamma. LTC4S expression was further upregulated by treatment with troglitazone, a PPAR gamma agonist. Promoter-luciferase and chromatin immunoprecipitation assays showed that PPAR gamma directly bound to the PPAR response element of the LTC4S gene promoter in adipocytes. These results indicate that the LTC4S gene expression was enhanced by PPAR gamma, and LTC4 and LTD4 activated adipogenesis through CysLT1 receptors in 3T3-L1 cells. Thus, LTC4S and CysLT1 receptors are novel potential targets for the treatment of obesity.