Journal
MOLECULAR IMMUNOLOGY
Volume 116, Issue -, Pages 18-28Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2019.09.006
Keywords
lncRNA H19; miR-675; HBx; Liver cell injury; PPAR alpha; AkT/mTOR signalling
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Funding
- Shandong Provincial Natural Science Foundation, China [ZR2016HM52]
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Emerging evidence indicates that the lncRNAs/microRNA/mRNA axis plays important roles in a variety of diseases. This study was aimed to investigate the potential roles and underlying molecular mechanisms of lncRNA H19 and H19-derived miR-675 in regulating hepatitis B virus (HBV)-associated liver injury. mRNA and miR-675 levels were determined by quantitative real-time PCR (qRT-PCR), protein levels were determined by western blot, cell viability was measured by the MTT assay, cell apoptosis was measured by flow cytometry, inflammatory cytokine production was determined by ELISA, oxidative stress and energy metabolism were assessed by commercial kits, and the target relationship between PPARa and miR-675 was confirmed by the dualluciferase reporter assay. The results showed that the expression of lncRNA H19 and miR-675 was up-regulated in patients with chronic hepatitis B (n = 20). Inhibition of lncRNA H19 or miR-675 in L02 cells lncreased cell viability, suppressed hepatitis B X protein (HBx)-induced cell apoptosis, inflammatory cytokine production, and oxidative stress, and remodelled energy metabolism. Furthermore, PPAR alpha was found to be a target gene of miR-675. The expression of PPAR alpha was down-regulated in patients with chronic hepatitis B, and there was a negative correlation between the expression of lncRNA H19 and PPAR alpha, or between miR-675 and PPAR alpha. Moreover, by knocking down the expression of PPAR alpha, the actions (apoptosis, inflammatory factors, oxidative stress, and energy metabolism) of lncRNA H19 or miR-675 inhibition in HBx-induced L02 cells were at least partially reversed. In addition, HBx-induced elevated levels of p-Akt(Ser473), p-Akt(Thr308) and p-mTOR(Ser2448) were down-regulated by lncRNA H19 or miR-675 inhibition. Furthermore, PPAR alpha knockdown partly reversed the down regulated effects of H19 or miR-675 inhibition. Taken together, these data indicate that the lncRNA H19/miR675/PPAR alpha axis regulates liver cell injury and energy metabolism remodelling induced by HBx, which may be related to the modulation of Akt/mTOR signalling.
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