NF-κB essential modifier is required for hepatocyte proliferation and the oval cell reaction after partial hepatectomy in mice.

Abstract

BACKGROUND & AIMS:

The transcription factor nuclear factor κB (NF-κB) is activated by the IκB kinase complex. The regulatory subunit of this complex, NF-κB essential modifier (NEMO or IKBKG), is a tumor suppressor. Hepatocyte-specific deletion of NEMO induces chronic liver inflammation that leads to apoptosis, oxidative stress, development of nonalcoholic steatohepatitis, and hepatocarcinogenesis.

METHODS:

We performed partial hepatectomies in mice with hepatocyte-specific disruption of NEMO (Nemo(Δhepa)). Some mice were fed a diet that contained the antioxidant butylated hydroxyanisole (BHA), and others were given daily intraperitoneal injections of the oxidant phenetyl isothiocyanate (PEITC).

RESULTS:

Nemo(Δhepa) mice had impaired liver regeneration after partial hepatectomy and 50% mortality, indicating that NEMO is required for the regenerative response. Liver cells of the mice had a strong oxidative stress response; these cells down-regulated the NF-κB-dependent antioxidant response and reduced levels of proteins that repair DNA double-strand breaks. However, the impairments to hepatocyte proliferation were compensated by a response of oval cells in Nemo(Δhepa) mice. Oval cells expressed low levels of albumin and thereby expressed normal levels of NEMO. Repopulation of the liver with oval cells that expressed NEMO reversed liver damage in Nemo(Δhepa) mice. Interestingly, these mice still developed hepatocellular carcinomas 6 months after partial hepatectomy, whereas Nemo(Δhepa) mice fed the BHA diet were protected from carcinogenesis.

CONCLUSIONS:

In livers of mice, expression of NEMO and activation of NF-κB are required for hepatocyte proliferation and liver regeneration. These mechanisms require control of oxidative stress and DNA integrity.

• Authors: Yann Malato, Haksier Ehedego, Malika Al-Masaoudi, Francisco Javier Cubero, Jörn Bornemann, Nikolaus Gassler, Christian Liedtke, Naiara Beraza, Christian Trautwein
• Journal: Gastroenterology (Gastroenterology) Vol. 143 Issue 6 Pg. 1597-1608.e11 (Dec 2012) ISSN: 1528-0012 [Electronic] United States
• PMID: 22922425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Intracellular Signaling Peptides and Proteins
• NEMO protein, mouse
• NF-kappa B
• Butylated Hydroxyanisole

Topics

• Animals
• Antioxidants (pharmacology, therapeutic use)
• Apoptosis (physiology)
• Butylated Hydroxyanisole (pharmacology, therapeutic use)
• Cell Proliferation
• Disease Models, Animal
• Hepatectomy
• Hepatocytes (cytology)
• Intracellular Signaling Peptides and Proteins (deficiency, genetics, physiology)
• Liver (cytology, physiology, surgery)
• Liver Neoplasms, Experimental (pathology, prevention & control)
• Liver Regeneration (drug effects, physiology)
• Male
• Mice
• Mice, Mutant Strains
• NF-kappa B (physiology)
• Oxidative Stress (physiology)
• Phenotype