PGE2 induces apoptosis of hepatic stellate cells and attenuates liver fibrosis in mice by downregulating miR-23a-5p and miR-28a-5p
PGE2 induces apoptosis of hepatic stellate cells and attenuates liver fibrosis in mice by downregulating miR-23a-5p and miR-28a-5p
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DOI：
10.1016/j.bbadis.2017.11.001
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发表时间：
2018-02-01
影响因子：
6.2
通讯作者：
Agra, N.
中科院分区：
文献类型：
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作者：
Brea, R.;Motino, O.;Agra, N.
MicroRNA（miRNAs）是一种调节信使RNA（mRNA）和蛋白质表达的小的非编码RNA，已成为慢性肝病的关键调控分子，其终末期是肝纤维化，这是一个主要的全球健康负担。预防或治疗肝纤维化的药理学策略仍然有限，这使得有必要更好地了解其发病机制的分子机制。在这种情况下，我们最近发现，环氧合酶-2（考克斯-2）在肝细胞中的表达限制了肝星状细胞（HSC）的活化，这是肝纤维化发生和发展的关键事件。在此，我们评估了考克斯-2在CCl 4和胆管结扎（BDL）诱导的肝纤维化小鼠模型中对一组特定miRNA的调节作用。我们的研究结果为考克斯-2抑制HSC中miR-23 a-5 p和miR-28- 5 p的表达提供了证据。miR-23 a-5 p和miR-28- 5 p表达的降低通过降低促纤维化标志物α-SMA和COL 1A 1的水平和增加HSC的凋亡来促进针对纤维化的保护。此外，我们证明了慢性肝病患者的血清miR-28- 5 p水平降低。这些结果表明考克斯-2衍生的前列腺素类在肝纤维化过程中发挥保护作用。
MicroRNAs (miRNAs), small noncoding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key regulatory molecules in chronic liver diseases, whose end stage is hepatic fibrosis, a major global health burden. Pharmacological strategies for prevention or treatment of hepatic fibrosis are still limited, what makes it necessary to establish a better understanding of the molecular mechanisms underlying its pathogenesis. In this context, we have recently shown that cyclooxygenase-2 (COX-2) expression in hepatocytes restricts activation of hepatic stellate cells (HSCs), a pivotal event in the initiation and progression of hepatic fibrosis. Here, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs on a mouse model of CCl4 and bile duct ligation (BDL)-induced liver fibrosis. Our results provide evidence that COX-2 represses miR-23a-5p and miR-28-5p expression in HSC. The decrease of miR-23a-5p and miR-28-5p expression promotes protection against fibrosis by decreasing the levels of pro-fibrogenic markers alpha-SMA and COL1A1 and increasing apoptosis of HSC. Moreover, we demonstrate that serum levels of miR-28-5p are decreased in patients with chronic liver disease. These results suggest a protective effect exerted by COX-2-derived prostanoids in the process of hepatofibrogenesis.