Sasaki Reina, Sur Subhayan, Cheng Qi, Steele Robert, Ray Ratna B
Department of Pathology Saint Louis University St Louis MO.
Saint Louis University Liver Center Saint Louis University St Louis MO.
Hepatol Commun. 2019 Apr 25;3(7):943-953. doi: 10.1002/hep4.1362. eCollection 2019 Jul.
Chronic hepatitis C virus (HCV) infection often leads to end-stage liver disease, including hepatocellular carcinoma (HCC). We have previously observed reduced expression of microRNA-30e (miR-30e) in the liver tissues and sera of patients with HCV-associated HCC, although biological functions remain unknown. In this study, we demonstrated that HCV infection of hepatocytes transcriptionally reduces miR-30e expression by modulating CCAAT/enhancer binding protein β. prediction suggests that autophagy-related gene 5 (ATG5) is a direct target of miR-30e. ATG5 is involved in autophagy biogenesis, and HCV infection in hepatocytes induces autophagy. We showed the presence of ATG5 in the miR-30e-Argonaute 2 RNA-induced silencing complex. Overexpression of miR-30e in HCV-infected hepatocytes inhibits autophagy activation. Subsequent studies suggested that ATG5 knockdown in Huh7.5 cells results in the remarkable inhibition of sterol regulatory element binding protein (SREBP)-1c and fatty acid synthase (FASN) level. We also showed that overexpression of miR-30e decreased lipid synthesis-related protein SREBP-1c and FASN in hepatocytes. : We show new mechanistic insights into the interactions between autophagy and lipid synthesis through inhibition of miR-30e in HCV-infected hepatocytes.
慢性丙型肝炎病毒（HCV）感染常导致终末期肝病，包括肝细胞癌（HCC）。我们之前观察到，HCV相关HCC患者的肝组织和血清中微小RNA-30e（miR-30e）表达降低，但其生物学功能尚不清楚。在本研究中，我们证明肝细胞的HCV感染通过调节CCAAT/增强子结合蛋白β转录降低miR-30e表达。预测表明自噬相关基因5（ATG5）是miR-30e的直接靶点。ATG5参与自噬生物发生，肝细胞中的HCV感染诱导自噬。我们发现ATG5存在于miR-30e-AGO2 RNA诱导沉默复合体中。在HCV感染的肝细胞中过表达miR-30e可抑制自噬激活。随后的研究表明，在Huh7.5细胞中敲低ATG5可显著抑制固醇调节元件结合蛋白（SREBP）-1c和脂肪酸合酶（FASN）水平。我们还表明，miR-30e过表达可降低肝细胞中脂质合成相关蛋白SREBP-1c和FASN的水平。我们通过抑制HCV感染肝细胞中的miR-30e，揭示了自噬与脂质合成之间相互作用的新机制。
