Publikationsserver der RWTH Aachen University
Role of the IKK complex during liver regeneration
Abstract
dc:descriptionThe transcription factor NF-kB is essential for liver homeostasis. The IKK complex (composed by two catalytic subunits IKK1 and IKK2 and a regulatory subunit Nemo) tightly regulates NF-kB activity. In the present work, we modulated NF-kB activity in the liver by using hepatocyte-specific IKK2 (IKK2dhepa) and hepatocyte-specific Nemo (Nemodhepa) knockout mice and analyzed the role of the IKK complex in the context of liver regeneration. Partial hepatectomy (PH) in IKK2dhepa mice led to a delayed and reduced NF-kB activation. Consequently, the proinflammatory cytokine TNF-alpha was strongly induced earlier in IKK2dhepa mice and the Acute Phase Response marker SAA showed an early and strong mRNA activation in KO compared to WT mice. In addition, PolyMorphoNuclear cells were recruited massively in IKK2dhepa liver 12h after hepatectomy. As a result of all these early events, IKK2dhepa mice showed earlier hepatocytes proliferation compared to wt animals. These mechanisms would contribute to faster liver regeneration observed in IKK2dhepa mice. 50% of Nemodhepa mice died during the regeneration process while all WT animals survived as expected. After PH, priming was impaired in Nemodhepa mice with TNF-alpha and IL-6 liver protein levels both downregulated. This led to a blunted kinetic during liver regeneration in Nemodhepa mice with a low and constant rate of proliferation. Furthermore, oval cells were unusually activated shortly after PH in Nemodhepa mice, highlighting an important role for this cell population. Oxidative stress plays an important role in Nemodhepa mice livers before and especially after liver surgery. Butylated hydroxyanisole (BHA, an antioxidant) supplemented diet resulted in a significantly reduced liver damage before and after PH. Additionally, BHA feeding restored hepatocyte proliferation in Nemodhepa livers and resulted in 100% survival after PH. In contrast, mice treated for 1 week with phenethyl isothiocyanate (PEITC), an oxidative stress inducer, showed significantly higher liver damage after PH and moreover, all PEITC-treated Nemodhepa mice died within 3 days after PH. Partial hepatectomy is highly challenging for Nemodhepa mice. Modulating the oxidative stress level directs the outcome of Nemodhepa mice after partial hepatecomy. By adapting the proliferative response, oxidative stress has a major impact on the phenotype observed in these animals.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2009
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Malato, Yann
- Contributors dc:contributor
-
- Trautwein, Christian
Subjects
dc:subject × 9Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng