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Edited by Tamas DalmayKeywords: miR-148a miR-30a Tail interacting protein of 47kDa Lipid droplets HCV a b s t r a c tThis study aimed at identifying potential microRNAs that modulate hepatic lipid droplets (LD) through targeting the Tail interacting protein of 47kDa (TIP47) in HCV infection.Bioinformatics analysis revealed that miR-148a and miR-30a potentially target TIP47. Expression profiling showed that both microRNAs were downregulated, while TIP47 was upregulated in liver biopsies of HCV-infected patients. Forcing the expression of both microRNAs in JFH-I infected, oleic acid-treated Huh7 cells, significantly suppressed TIP47 expression and reduced cellular LDs with marked decrease in viral RNA. This study shows that miR-148a and miR-30a, regulate TIP47 expression and LDs in HCV infected cells.

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IntroductionIncreased de novo lipogenesis (DNL) is one of the key factors contributing to fat accumulation and non-alcoholic fatty liver disease (NAFLD). Among the critical transcription factors (TFs) regulating DNL is mTOR and its downstream lipogenic TF, SREBP1c. In recent years, it has been established that non-coding RNAs (ncRNAs) play role in both biological processes and disease pathogenesis. Our group has previously characterized microRNAs that can target and regulate the expression of both mTOR and SREBP1c. Accordingly, this study aimed to broaden our understanding of the role of ncRNAs in regulating the mTOR/SREBP1c axis to elucidate the role of the non-coding transcriptome in DNL and lipid droplet (LD) formation. Hence, short ncRNA, miR-615-5p, and long non-coding RNA (lncRNA), H19, were chosen as they were previously proven to target mTOR by our group and in the published literature, respectively.MethodologyHuh-7 cells were treated with 800 μM oleic acid (OA) to promote LD formation. Transfection of miR-615-5p mimics or H19 over-expression vectors was performed, followed by the measurement of their downstream targets, mTOR and SREBP, on the mRNA level by quantitative real-time PCR (qRT-PCR), and on the protein level by Western blot. To determine the functional impact of miR-615-5p and H19 on LD formation and triglyceride (TG) accumulation, post-transfection LDs were stained, imaged, and characterized, and TGs were extracted and quantified.ResultsmiR-615-5p was able to reduce mTOR and SREBP1c significantly on both the mRNA and protein levels compared to control cells, while H19 caused a reduction of both targets on the protein level only. Both miR-615-5p and H19 were able to significantly reduce the LD count and total area, as well as TG levels compared to control cells.ConclusionTo conclude, this study shows, for the first time, the impact of miR-615-5p and H19 on the mTOR/SREBP1c axis, and thus, their functional impact on LDs and TG accumulation. These findings might pave the way for using ncRNAs as potential therapeutic targets in the management of fatty liver.