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Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis
BACKGROUND: The NF-kB signaling, regulated by IKK1-p52/RelB and IKK2-p65, is activated by various stresses to protect or damage the liver, in context-specific manners. Two previous studies of liver-specific expression of constitutive active IKK2 (IKK2ca) showed that strong activation of IKK2-NF-kB i...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518658/ https://www.ncbi.nlm.nih.gov/pubmed/26219821 http://dx.doi.org/10.1186/s12876-015-0325-z |
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author | Lu, Hong Lei, Xiaohong Zhang, Qinghao |
author_facet | Lu, Hong Lei, Xiaohong Zhang, Qinghao |
author_sort | Lu, Hong |
collection | PubMed |
description | BACKGROUND: The NF-kB signaling, regulated by IKK1-p52/RelB and IKK2-p65, is activated by various stresses to protect or damage the liver, in context-specific manners. Two previous studies of liver-specific expression of constitutive active IKK2 (IKK2ca) showed that strong activation of IKK2-NF-kB in mouse livers caused inflammation, insulin resistance, and/or fibrosis. The purpose of this study was to understand how moderate activation of IKK2-NF-kB in adult mouse livers alters hepatic gene expression and pathophysiology. METHOD: We generated mice with adult hepatocyte-specific activation of Ikk2 (Liv-Ikk2ca) using Alb-cre mice and Ikk2ca Rosa26 knockin mice in which a moderate expression of Ikk2ca transgene was driven by the endogenous Rosa26 promoter. RESULTS: Surprisingly, compared to wild-type mice, adult male Liv-Ikk2ca mice had higher hepatic mRNA expression of Ikk2 and classical NF-kB targets (e.g. Lcn2 and A20), as well as IKK1, NIK, and RelB, but no changes in markers of inflammation or fibrosis. Blood levels of IL-6 and MCP-1 remained unchanged, and histology analysis showed a lack of injury or infiltration of inflammatory cells in livers of Liv-Ikk2ca mice. Moreover, Liv-Ikk2ca mice had lower mRNA expression of prooxidative enzymes Cyp2e1 and Cyp4a14, higher expression of antioxidative enzymes Sod2, Gpx1, and Nqo1, without changes in key enzymes for fatty acid oxidation, glucose utilization, or gluconeogenesis. In parallel, Liv-Ikk2ca mice and wild-type mice had similar levels of hepatic reduced glutathione, endogenous reactive oxygen species, and lipid peroxidation. Additionally, Liv-Ikk2ca mice had higher Cyp3a11 without down-regulation of most drug processing genes. Regarding nuclear proteins of NF-kB subunits, Liv-Ikk2ca mice had moderately higher p65 and p50 but much higher RelB. Results of ChIP-qPCR showed that the binding of p50 to multiple NF-kB-target genes was markedly increased in Liv-Ikk2ca mice. Additionally, Liv-Ikk2ca mice had moderate increase in triglycerides in liver, which was associated with higher lipogenic factors Pparγ, Lxr, Fasn, Scd1, and CD36. CONCLUSION: In summary, moderate activation of IKK2-NF-kB in unstressed adult mouse hepatocytes produces a cytoprotective gene expression profile and induces lipogenesis without apparent signs of inflammation or fibrosis, likely due to strong activation of the anti-inflammatory IKK1-RelB alternative NF-kB pathway as well as the Lxr. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12876-015-0325-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4518658 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45186582015-07-30 Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis Lu, Hong Lei, Xiaohong Zhang, Qinghao BMC Gastroenterol Research Article BACKGROUND: The NF-kB signaling, regulated by IKK1-p52/RelB and IKK2-p65, is activated by various stresses to protect or damage the liver, in context-specific manners. Two previous studies of liver-specific expression of constitutive active IKK2 (IKK2ca) showed that strong activation of IKK2-NF-kB in mouse livers caused inflammation, insulin resistance, and/or fibrosis. The purpose of this study was to understand how moderate activation of IKK2-NF-kB in adult mouse livers alters hepatic gene expression and pathophysiology. METHOD: We generated mice with adult hepatocyte-specific activation of Ikk2 (Liv-Ikk2ca) using Alb-cre mice and Ikk2ca Rosa26 knockin mice in which a moderate expression of Ikk2ca transgene was driven by the endogenous Rosa26 promoter. RESULTS: Surprisingly, compared to wild-type mice, adult male Liv-Ikk2ca mice had higher hepatic mRNA expression of Ikk2 and classical NF-kB targets (e.g. Lcn2 and A20), as well as IKK1, NIK, and RelB, but no changes in markers of inflammation or fibrosis. Blood levels of IL-6 and MCP-1 remained unchanged, and histology analysis showed a lack of injury or infiltration of inflammatory cells in livers of Liv-Ikk2ca mice. Moreover, Liv-Ikk2ca mice had lower mRNA expression of prooxidative enzymes Cyp2e1 and Cyp4a14, higher expression of antioxidative enzymes Sod2, Gpx1, and Nqo1, without changes in key enzymes for fatty acid oxidation, glucose utilization, or gluconeogenesis. In parallel, Liv-Ikk2ca mice and wild-type mice had similar levels of hepatic reduced glutathione, endogenous reactive oxygen species, and lipid peroxidation. Additionally, Liv-Ikk2ca mice had higher Cyp3a11 without down-regulation of most drug processing genes. Regarding nuclear proteins of NF-kB subunits, Liv-Ikk2ca mice had moderately higher p65 and p50 but much higher RelB. Results of ChIP-qPCR showed that the binding of p50 to multiple NF-kB-target genes was markedly increased in Liv-Ikk2ca mice. Additionally, Liv-Ikk2ca mice had moderate increase in triglycerides in liver, which was associated with higher lipogenic factors Pparγ, Lxr, Fasn, Scd1, and CD36. CONCLUSION: In summary, moderate activation of IKK2-NF-kB in unstressed adult mouse hepatocytes produces a cytoprotective gene expression profile and induces lipogenesis without apparent signs of inflammation or fibrosis, likely due to strong activation of the anti-inflammatory IKK1-RelB alternative NF-kB pathway as well as the Lxr. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12876-015-0325-z) contains supplementary material, which is available to authorized users. BioMed Central 2015-07-30 /pmc/articles/PMC4518658/ /pubmed/26219821 http://dx.doi.org/10.1186/s12876-015-0325-z Text en © Lu et al. 2015 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Lu, Hong Lei, Xiaohong Zhang, Qinghao Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
title | Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
title_full | Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
title_fullStr | Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
title_full_unstemmed | Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
title_short | Moderate activation of IKK2-NF-kB in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
title_sort | moderate activation of ikk2-nf-kb in unstressed adult mouse liver induces cytoprotective genes and lipogenesis without apparent signs of inflammation or fibrosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518658/ https://www.ncbi.nlm.nih.gov/pubmed/26219821 http://dx.doi.org/10.1186/s12876-015-0325-z |
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