Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
Cells. 2023 Jul 13;12(14):1845. doi: 10.3390/cells12141845.
Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration, and fibrosis, NASH, at a molecular level, involves lipid-induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen for NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage induced by lipotoxicity results in the release of extracellular RNAs (eRNAs), which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravate inflammation, and lead to cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increases cellular viability and reduces NF-kB-mediated cytokine production. Similarly, RNase 1 administration significantly improves hepatic steatosis, inflammatory and injury markers in a murine NASH model. Therefore, this study, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.
非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病（NAFLD）的严重临床阶段。从组织学上看，NASH 的特征是肝细胞气球样变、免疫细胞浸润和纤维化，在分子水平上涉及脂质诱导的肝细胞死亡和细胞因子的产生。目前，用于筛查 NASH 的诊断生物标志物非常少，也没有针对其治疗的药物干预措施。在这项研究中，我们表明，脂肪毒性诱导的肝细胞损伤导致细胞外 RNA（eRNA）的释放，这些 RNA 作为损伤相关分子模式（DAMPs），刺激促凋亡和促炎细胞因子的表达，加重炎症，并导致 HepG2 细胞死亡。此外，核糖核酸酶 1 抑制 eRNA 活性可显著增加细胞活力并减少 NF-kB 介导的细胞因子产生。同样，核糖核酸酶 1 的给药可显著改善 NASH 小鼠模型中的肝脂肪变性、炎症和损伤标志物。因此，这项研究首次强调了抑制 eRNA 作用作为治疗 NASH 的新策略的治疗潜力。
