PUBLICATION
Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish
- Authors
- Lai, C.Y., Lin, C.Y., Hsu, C.C., Yeh, K.Y., Her, G.M.
- ID
- ZDB-PUB-180422-3
- Date
- 2018
- Source
- Biochimica et biophysica acta 1863(8): 844-856 (Journal)
- Registered Authors
- Her, Guor Muor
- Keywords
- Lipogenesis, Nonalcoholic fatty liver disease, Steatosis, microRNA sponge
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Biosynthetic Pathways/genetics*
- Cell Line
- Disease Models, Animal*
- Female
- Humans
- Lipogenesis/genetics*
- Liver/metabolism
- Liver/pathology
- Male
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/metabolism*
- Non-alcoholic Fatty Liver Disease/genetics*
- Non-alcoholic Fatty Liver Disease/pathology
- Oncorhynchus mykiss
- PPAR gamma/antagonists & inhibitors
- PPAR gamma/metabolism
- Protein Stability
- Transcription Factor CHOP/metabolism
- YY1 Transcription Factor/genetics*
- YY1 Transcription Factor/metabolism
- Zebrafish*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 29678641 Full text @ Biochim. Biophys. Acta
Citation
Lai, C.Y., Lin, C.Y., Hsu, C.C., Yeh, K.Y., Her, G.M. (2018) Liver-directed microRNA-7a depletion induces nonalcoholic fatty liver disease by stabilizing YY1-mediated lipogenic pathways in zebrafish. Biochimica et biophysica acta. 1863(8):844-856.
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been associated with the function and changes in expression levels of microRNAs (miRs). MiR-7 has been proven to play an important role in many cellular processes; however, its functions in the context of liver lipogenesis remain unknown. We applied the microRNA-sponge (miR-SP) technology and generated transgenic miR-7a-SP models (hC7aSP and bC7aSP), which disrupted the activities of hepatic miR-7a and induced the early onset of NAFLD and nonalcoholic steatohepatitis (NASH) in zebrafish. We identified a novel miR-7a target, YY1, and demonstrated novel miR-7a functions to regulate zebrafish hepatic lipid metabolism by controlling YY1 stabilization through the regulation of the expression of lipogenic signaling pathways. Correspondingly, liver specific miR-7a depletion functionally promoted lipid accumulation in hC7ASP livers. NASH hC7aSP increased the expression of inflammatory genes (il-1b, il-6, tnf-α, ifn-γ, nfkb2, and NF-kB) and endoplasmic reticulum stress markers (atf6, ern2, ire1, perk, hspa5 and ddit3). Molecular analysis revealed that miR-7a-SP can stabilize YY1 expression and contribute to the accumulation of hepatic triglycerides by reducing the CHOP-10 expression in the hC7aSP and then inducing the transactivation of C/EBP-α and PPAR-γ expression. PPAR-γ antagonists and miR-7a mimic treatment ameliorate hC7aSP NASH phenotypes.
Conclusion Our results suggest that miR-7a-SP acts as a lipid enhancer by directly increasing YY1 stability to disrupt CHOP-10-dependent suppression of lipogenic pathways, resulting in increased lipid accumulation. MiR-7a expression improves liver steatosis and steatohepatitis in hC7aSPs, which suggests a novel strategy for the prevention and early treatment of NASH in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping