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Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse

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Abstract

Recent studies have reported that NF-κB mediated down-regulation of miRNA-29 and lower expression of miRNA-29 promoted the deposition of collagens in fibrotic liver. Our previous research demonstrated that the increased Hedgehog (Hh) signaling, a key regulator for hepatic fibrogenesis, induced the severe hepatic fibrosis in the livers with impaired NF-κB signaling. These findings led us to investigate the effect of Hh and miRNA-29 on the hepatic fibrosis under dysregulated NF-κB signaling. In this study, we used IKKβF/F and IKKβ-deficient IKKβΔHEP mouse model with a defective NF-κB signaling pathway, and assessed the expression of the miRNA-29 family (miRNA-29a, miRNA-29b, and miRNA-29c), Hh, and proliferation of MF-HSCs in liver from IKKβF/F mice and IKKβΔHEP mice both before and after MCDE treatment. The activation of NF-κB was significantly increased in MCDE diet-fed IKKβF/F mice compared to IKKβΔHEP mice. Expression of miRNA-29 family was greater in MCDE diet-fed IKKβΔHEP mice than IKKβF/F mice, demonstrating that the impaired NF-κB pathway was unable to suppress the expression of miRNA-29s after injury. However, expression of the Hh signaling pathway was greatly enhanced, and activation of Hh promoted the accumulation of MF-HSCs with impaired NF-κB, eventually increasing fibrogenesis in the damaged liver of IKKβΔHEP mice. Therefore, these results demonstrated that Hh signaling regulates the proliferation of MF-HSCs irrespective of the action of miRNA-29, eventually contributing hepatic fibrosis, when the NF-κB pathway is disrupted.

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Abbreviations

Alb:

Albumin

α-SMA:

Alpha smooth muscle actin

DAB:

Diaminobenzidine

ECM:

Extracellular matrix

Gli:

Glioblastoma

Hh:

Hedgehog

HIP:

Hedgehog-interacting protein

HSC:

Hepatic stellate cell

IκB:

Inhibitor of kappa B

IKK:

IκB kinase

LPS:

Lipopolysaccharide

MCDE:

Methionine/choline-deficient diet supplemented with 0.15 % ethionine

MF-HSC:

Myofibroblastic hepatic stellate cell

miRNA:

MicroRNA

NF-κB:

Nuclear factor kappa B

Q-HSC:

Quiescent hepatic stellate cell

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Acknowledgments

This work was supported by the Bio-Scientific Research Grant funded by the Pusan National University (PNU, Bio-Scientific Research Grant) (PNU-2010-101-250).

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Biological Sciences, College of Natural Science, Pusan National University, Pusandaehak-ro 63 beon-gil, Geumjeong-gu, Pusan, 609-735, Korea

    Jeongeun Hyun & Youngmi Jung

  2. Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC, USA

    Steve S. Choi & Anna Mae Diehl

Authors
  1. Jeongeun Hyun
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  2. Steve S. Choi
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  3. Anna Mae Diehl
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  4. Youngmi Jung
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Correspondence to Youngmi Jung.

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Hyun, J., Choi, S.S., Diehl, A.M. et al. Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse. J Mol Hist 45, 103–112 (2014). https://doi.org/10.1007/s10735-013-9532-5

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  • DOI: https://doi.org/10.1007/s10735-013-9532-5

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