1. The increase of long noncoding RNA Fendrr in hepatocytes contributes to liver fibrosis by promoting IL-6 production.
- Author
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Kang Z, Wang C, Shao F, Deng H, Sun Y, Ren Z, Zhang W, Ding Z, Zhang J, and Zang Y
- Subjects
- Animals, Humans, Male, Mice, Carbon Tetrachloride toxicity, Hepatic Stellate Cells metabolism, Hepatic Stellate Cells pathology, Mice, Inbred C57BL, STAT2 Transcription Factor metabolism, STAT2 Transcription Factor genetics, Hepatocytes metabolism, Hepatocytes pathology, Interleukin-6 metabolism, Interleukin-6 genetics, Liver Cirrhosis metabolism, Liver Cirrhosis genetics, Liver Cirrhosis pathology, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
Liver fibrosis/cirrhosis is a pathological state caused by excessive extracellular matrix deposition. Sustained activation of hepatic stellate cells (HSC) is the predominant cause of liver fibrosis, but the detailed mechanism is far from clear. In this study, we found that long noncoding RNA Fendrr is exclusively increased in hepatocytes in the murine model of CCl
4 - and bile duct ligation-induced liver fibrosis, as well as in the biopsies of liver cirrhosis patients. In vivo, ectopic expression of Fendrr aggravated the severity of CCl4 -induced liver fibrosis in mice. In contrast, inhibiting Fendrr blockaded the activation of HSC and ameliorated CCl4 -induced liver fibrosis. Our mechanistic study showed that Fendrr binds to STAT2 and enhances its enrichment in the nucleus, which then promote the expression of interleukin 6 (IL-6), and, ultimately, activates HSC in a paracrine manner. Accordingly, disrupting the interaction between Fendrr and STAT2 by ectopic expression of a STAT2 mutant attenuated the profibrotic response inspired by Fendrr in the CCl4 -induced liver fibrosis. Notably, the increase of Fendrr in patient fibrotic liver is positively correlated with the severity of fibrosis and the expression of IL-6. Meanwhile, hepatic IL-6 positively correlates with the extent of liver fibrosis and HSC activation as well, thus suggesting a causative role of Fendrr in HSC activation and liver fibrosis. In conclusion, these observations identify an important regulatory cross talk between hepatocyte Fendrr and HSC activation in the progression of liver fibrosis, which might represent a potential strategy for therapeutic intervention., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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