Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
J Hepatol. 2019 Apr;70(4):722-734. doi: 10.1016/j.jhep.2018.12.016. Epub 2018 Dec 22.
BACKGROUND & AIMS: Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive.
Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis.
Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis.
Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.
Liver fibrosis majorly contributes to mortality resulting from various liver diseases. We discovered a small RNA known as miRNA-221-3p, whose downregulation in hepatocytes results in reduced liver fibrosis. Thus, inhibition of miRNA-221-3p may serve as one of the therapeutic approaches for treatment of liver fibrosis.
纤维化是肝功能失调的主要特征，它显著导致了越来越多的终末期慢性肝病患者的死亡。肝细胞与肝星状细胞（HSCs）之间的串扰在纤维化的进展中起着关键作用。尽管人们已经付出了大量的努力来阐明 HSCs 在肝纤维化过程中的功能，但肝细胞的调节功能仍然难以捉摸。
我们采用无偏见的功能微小 RNA（miRNA）筛选方法，通过 miRNA 调节来研究肝细胞通过精细调控基因表达来调节纤维化的能力。通过使用腺相关病毒在四氯化碳和 3,5-二乙氧基羰基-1,4-二氢可待因诱导的肝纤维化中抑制肝细胞中的 miRNA，进行了体内功能分析。
在慢性肝损伤期间阻断肝细胞中的 miRNA-221-3p 功能可促进肝脏恢复和更快地解决沉积的细胞外基质。此外，我们证明，由于 miRNA-221-3p 对 GNAI2（G 蛋白 alpha 抑制活性多肽 2）的转录后调节，导致 C-C 基序趋化因子配体 2 的分泌减少，从而减轻了肝纤维化。
综上所述，肝细胞中的 miRNA 调节，作为肝脏中易于靶向的细胞类型，可能成为肝纤维化的潜在治疗方法。
肝纤维化是导致各种肝病患者死亡的主要原因。我们发现了一种称为 miRNA-221-3p 的小 RNA，其在肝细胞中的下调导致肝纤维化减少。因此，抑制 miRNA-221-3p 可能成为治疗肝纤维化的一种治疗方法。
