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NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.

Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S, Van TM, Curth HM, Heise N, Weih F, Klein U, Schirmacher P, Kelliher M, Pasparakis M - Cancer Cell (2015)

Bottom Line: Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer.Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice.Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.

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Mice with LPC-Specific NF-κB Inhibition Do Not Develop HCC(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B) Liver to body weight (LW/BW) ratios in 52-week-old mice with the indicated genotypes. Horizontal lines indicate mean values.(C) Serum ALT levels in 52-week-old mice with the indicated genotypes. The ALT values of NF-κBLPC-KO mice with very small (<2 mm diameter) macroscopically visible nodules are marked in red.(D) Representative images of liver sections from 52-week-old NF-κBLPC-KO, NEMOLPC-KO and floxed control mice stained with Masson's trichrome (collagen staining in blue) or immunostained with the indicated antibodies. HCC areas are outlined and marked with an asterisk. Graph shows quantification of Ki67+ cells (mean ± SD, n = 3–5 mice per genotype). Scale bars, 200 μm.See also Figure S2.
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fig2: Mice with LPC-Specific NF-κB Inhibition Do Not Develop HCC(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B) Liver to body weight (LW/BW) ratios in 52-week-old mice with the indicated genotypes. Horizontal lines indicate mean values.(C) Serum ALT levels in 52-week-old mice with the indicated genotypes. The ALT values of NF-κBLPC-KO mice with very small (<2 mm diameter) macroscopically visible nodules are marked in red.(D) Representative images of liver sections from 52-week-old NF-κBLPC-KO, NEMOLPC-KO and floxed control mice stained with Masson's trichrome (collagen staining in blue) or immunostained with the indicated antibodies. HCC areas are outlined and marked with an asterisk. Graph shows quantification of Ki67+ cells (mean ± SD, n = 3–5 mice per genotype). Scale bars, 200 μm.See also Figure S2.

Mentions: In contrast to NEMOLPC-KO mice, livers from 1-year-old mice with individual or combined LPC-specific deficiency of RelA, c-Rel, and RelB did not display macroscopic signs of tumor development, and only ∼25% (6 out of 25) of NF-κBLPC-KO mice showed a number of very small macroscopically visible steatotic nodules (Figure 2A). Accordingly, liver-to-body weight (LW/BW) ratio in NF-κBLPC-KO mice was similar to controls and significantly lower than that of NEMOLPC-KO mice (Figure 2B). One-year-old NF-κBLPC-KO mice showed significantly elevated serum ALT levels compared to controls but on average lower than NEMOLPC-KO mice (Figure 2C). Notably, ALT levels in NF-κBLPC-KO mice with macroscopically visible liver nodules were statistically higher compared to nodule-free mice (Figure 2C; 332 versus 135, p = 0.003), indicating that the appearance of small steatotic nodules correlated with increased liver damage.


NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis.

Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S, Van TM, Curth HM, Heise N, Weih F, Klein U, Schirmacher P, Kelliher M, Pasparakis M - Cancer Cell (2015)

Mice with LPC-Specific NF-κB Inhibition Do Not Develop HCC(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B) Liver to body weight (LW/BW) ratios in 52-week-old mice with the indicated genotypes. Horizontal lines indicate mean values.(C) Serum ALT levels in 52-week-old mice with the indicated genotypes. The ALT values of NF-κBLPC-KO mice with very small (<2 mm diameter) macroscopically visible nodules are marked in red.(D) Representative images of liver sections from 52-week-old NF-κBLPC-KO, NEMOLPC-KO and floxed control mice stained with Masson's trichrome (collagen staining in blue) or immunostained with the indicated antibodies. HCC areas are outlined and marked with an asterisk. Graph shows quantification of Ki67+ cells (mean ± SD, n = 3–5 mice per genotype). Scale bars, 200 μm.See also Figure S2.
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Show All Figures
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fig2: Mice with LPC-Specific NF-κB Inhibition Do Not Develop HCC(A) Representative liver images from 52-week-old mice with the indicated genotypes. Scale bar, 1 cm.(B) Liver to body weight (LW/BW) ratios in 52-week-old mice with the indicated genotypes. Horizontal lines indicate mean values.(C) Serum ALT levels in 52-week-old mice with the indicated genotypes. The ALT values of NF-κBLPC-KO mice with very small (<2 mm diameter) macroscopically visible nodules are marked in red.(D) Representative images of liver sections from 52-week-old NF-κBLPC-KO, NEMOLPC-KO and floxed control mice stained with Masson's trichrome (collagen staining in blue) or immunostained with the indicated antibodies. HCC areas are outlined and marked with an asterisk. Graph shows quantification of Ki67+ cells (mean ± SD, n = 3–5 mice per genotype). Scale bars, 200 μm.See also Figure S2.
Mentions: In contrast to NEMOLPC-KO mice, livers from 1-year-old mice with individual or combined LPC-specific deficiency of RelA, c-Rel, and RelB did not display macroscopic signs of tumor development, and only ∼25% (6 out of 25) of NF-κBLPC-KO mice showed a number of very small macroscopically visible steatotic nodules (Figure 2A). Accordingly, liver-to-body weight (LW/BW) ratio in NF-κBLPC-KO mice was similar to controls and significantly lower than that of NEMOLPC-KO mice (Figure 2B). One-year-old NF-κBLPC-KO mice showed significantly elevated serum ALT levels compared to controls but on average lower than NEMOLPC-KO mice (Figure 2C). Notably, ALT levels in NF-κBLPC-KO mice with macroscopically visible liver nodules were statistically higher compared to nodule-free mice (Figure 2C; 332 versus 135, p = 0.003), indicating that the appearance of small steatotic nodules correlated with increased liver damage.

Bottom Line: Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer.Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMO(LPC-KO) mice.Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMO(LPC-KO) mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931, Cologne, Germany.

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Related in: MedlinePlus