Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 15, Issue 1, Pages 93-104Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.28642
Keywords
hepatic stellate cell; histone deacetylase inhibitor; valproic acid; miRNA; proteomics
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Funding
- National Natural Science Foundation of China [81761128018, 81572871, 81141048, 81272027]
- Natural Science Foundation of Jiangsu Province [BK20151277]
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Reverting activated hepatic stellate cells (HSCs) to less activation or quiescent status is a promising strategy for liver fibrosis. Histone deacetylase inhibitor (HDACI) could suppress HSCs activation. Our previous study demonstrated a critical role of miRNAs in HSCs activation. Here, we explored the involvement of miRNAs in HDACI induced HSCs deactivation. Human cell line LX2 that resembled activated HSCs was treated with an HDACI - valproic acid (VPA). The effects of VPA on the protein and miRNA profile of LX2 were comprehensively analyzed by iTraq quantitative proteomics and miRNA microarray. The interaction between miRNA and proteins was investigated systematically. The biofunctions of differentially expressed proteins and miRNA targeted proteins were annotated. VPA treatment attenuated the activation phenotype of LX2. In VPA treated LX2, among 1548 quantified proteins, only 86 proteins were differentially expressed (VPA-proteins). While among 282 high-abundance miRNAs, 123 were differentially expressed (VPA-miRNAs), with 104 down-regulated and 19 up-regulated. The top biofunctions of VPA-proteins were closely related to HSCs activation, including cell death and survival, cell movement, cellular growth and proliferation. Furthermore, 22 out of the 36 VPA-proteins involved in cell death and survival, and 19 out of the 30 VPA-proteins involved in cellular movement were predicted targets of VPA-miRNAs. A direct regulatory effect of histone acetylation on miRNA expression was also established. In conclusion, our data provided the molecular mechanisms for VPA induced HSCs deactivation at the protein level and suggested crosstalk between histone acetylation and miRNAs in the inhibitory effects of HDACI on HSCs activation.
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