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
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.
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
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping