NF-κB signaling, liver disease and hepatoprotective agents

Sun, Beicheng; Karin, Michael

doi:10.1038/onc.2008.300

Cited by 287 publications

(215 citation statements)

References 177 publications

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“…Transcriptional activation of NF-kB induces low-grade inflammation and stimulates production of proinflammatory molecules, leading to insulin resistance and hepatic steatosis (23,24). In our study, we also detected an induction of the secretion of several cytokines and chemokines to the medium in adipose tissue explants in which NF-kB activity was increased by 5-LO products.…”

Section: Discussionsupporting

confidence: 71%

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

Horrillo

González-Périz

Martínez-Clemente

et al. 2010

The Journal of Immunology

131

137

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The presence of the so-called low-grade inflammatory state is recognized as a critical event in adipose tissue dysfunction, leading to altered secretion of adipokines and free fatty acids (FFAs), insulin resistance, and development of hepatic complications associated with obesity. This study was designed to investigate the potential contribution of the proinflammatory 5-lipoxygenase (5-LO) pathway to adipose tissue inflammation and lipid dysfunction in experimental obesity. Constitutive expression of key components of the 5-LO pathway, as well as leukotriene (LT) receptors, was detected in adipose tissue as well as in adipocyte and stromal vascular fractions. Adipose tissue from obese mice, compared with that from lean mice, exhibited increased 5-LO activating protein (FLAP) expression and LTB4 levels. Incubation of adipose tissue with 5-LO products resulted in NF-κB activation and augmented secretion of proinflammatory adipokines such as MCP-1, IL-6, and TNF-α. In addition, LTB4, but not LTD4, reduced FFA uptake in primary adipocytes, whereas 5-LO inhibition suppressed isoproterenol-induced adipose tissue lipolysis. In mice with dietary obesity, elevated FLAP expression in adipose tissue was paralleled with macrophage infiltration, increased circulating FFA levels, and hepatic steatosis, phenomena that were reversed by FLAP inhibition with Bay-X-1005. Interestingly, FLAP inhibition induced AMP-activated protein kinase phosphorylation in parallel with decreases in hormone-sensitive lipase activity and the expression and secretion of TNF-α and IL-6. Similar effects were observed in differentiated 3T3-L1 adipocytes incubated with either Bay-X-1005 or the selective LTB4 receptor antagonist U-75302. Taken together, these findings indicate that the 5-LO pathway signals the adipose tissue low-grade inflammatory state and steatogenic potential in experimental obesity.

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Section: Discussionsupporting

confidence: 71%

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

Horrillo

González-Périz

Martínez-Clemente

et al. 2010

The Journal of Immunology

131

137

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“…4,5 In relation to liver cancer, NF-kB signalling has been implicated in the pathogenesis of hepatitis, liver fibrosis, cirrhosis and HCC. 6,7 The IKK complex, composed of two catalytic subunits, IKK1/IKKa and IKK2/IKKb, and a regulatory subunit termed NEMO/IKKg, activates NF-kB by phosphorylating inhibitor of NF-kB (IkB) proteins targeting them for degradation by the proteasome and thus allowing the nuclear accumulation of NF-kB dimers. 5 IKK2 is primarily responsible for targeting and degrading IkBa thus inducing canonical NF-kB activation, although the two kinases show some degree of functional redundancy in controlling canonical NF-kB signalling.…”

mentioning

confidence: 99%

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKc, a subunit of the IjB kinase (IKK) complex that is essential for the activation of canonical NF-jB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO LPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO LPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMO LPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMOdeficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO LPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO LPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO LPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.

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“…6 In this regard, NF-B activity was also found in hepatocytes, where it regulates liver cell proliferation and survival during development, regeneration, and neoplastic transformation. 6,7 Under normal conditions, the various Rel/NF-B family members, RelA, RelB, c-Rel, NF-B1, and NF-B2 are sequestered in the cytoplasm because of physical interaction with inhibitors of NF-B (I Bs). 8,9 Viral infection, DNA damage, proinflammatory cytokines, and stress stimulate the I B kinase (IKK) complex, which comprises two catalytic subunits (IKK␣ and IKK␤) and a scaffold component (IKK␥).…”

mentioning

confidence: 99%

S100A8 and S100A9 Are Novel Nuclear Factor Kappa B Target Genes During Malignant Progression of Murine and Human Liver Carcinogenesis†

et al. 2009

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The nuclear factor-kappaB (NF-B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-B-deficient and NF-B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)H epatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumors arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes such as chronic hepatitis B and C viral infection, chronic alcohol consumption, and aflatoxin B1-contaminated food. 1,2 Despite remarkable improvements in diagnosis, only limited therapeutic options exist, most of them with minimal clinical benefit. 2 Moreover, there is

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NF-κB signaling, liver disease and hepatoprotective agents

Cited by 287 publications

References 177 publications

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

S100A8 and S100A9 Are Novel Nuclear Factor Kappa B Target Genes During Malignant Progression of Murine and Human Liver Carcinogenesis†

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