Potential role of Hedgehog signaling and microRNA-29 in liver fibrosis of IKKβ-deficient mouse.
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 IKKβ(F/F) and IKKβ-deficient IKKβ(ΔHEP) 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 IKKβ(F/F) mice and IKKβ(ΔHEP) mice both before and after MCDE treatment. The activation of NF-κB was significantly increased in MCDE diet-fed IKKβ(F/F) mice compared to IKKβ(ΔHEP) mice. Expression of miRNA-29 family was greater in MCDE diet-fed IKKβ(ΔHEP) mice than IKKβ(F/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 IKKβ(ΔHEP) 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.
Department of Biological Sciences, College of Natural Science, Pusan National University, Pusandaehak-ro 63 beon-gil, Geumjeong-gu, Pusan, 609-735, Korea.
Jeongeun
J
Hyun
Steve S
SS
Choi
Anna Mae
AM
Diehl
Youngmi
Y
Jung
D000818:Animals; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D051550:I-kappa B Kinase / Q000172:deficiency*; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction
D053823:Hedgehog Proteins; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse