Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Haybaeck, J; Stumptner, C; Thueringer, A; Kolbe, T; Magin, TM; Hesse, M; Fickert, P; Tsybrovskyy, O; Müller, H; Trauner, M; Zatloukal, K; Denk, H.
Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model.
Lab Invest. 2012; 92(6):857-867
Doi: 10.1038/labinvest.2012.49
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- Führende Autor*innen der Med Uni Graz
- Haybäck Johannes
- Co-Autor*innen der Med Uni Graz
- Denk Helmut
- Fickert Peter
- Müller Heimo
- Stumptner Cornelia
- Trauner Michael
- Tsybrovskyy Oleksiy
- Zatloukal Kurt
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- Abstract:
- Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8⁻/⁻ and krt18⁻/⁻ mice crossed into the same 129-ola genetic background were treated by acute and chronic administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8⁻/⁻ and krt18⁻/⁻ compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18⁻/⁻ mice already at an early stage of intoxication in contrast to krt8⁻/⁻ mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8⁻/⁻, krt18⁻/⁻ and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18⁻/⁻ and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8⁻/⁻ mice, steatosis was less, ballooning, and MDBs were absent. krt18⁻/⁻ mice developed MDBs whereas krt8⁻/⁻ mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. They are independent of the genetic background as an intrinsic factor. By contrast, toxicity effects may depend on the genetic background. krt8⁻/⁻ and krt18⁻/⁻ mice on the same genetic background show similar sensitivity to DDC intoxication and almost resemble wt animals regarding survival, degree of porphyria, liver-to-body weight ratio, serum bilirubin and liver enzyme levels. This stands in contrast to previous work where krt8⁻/⁻ and krt18⁻/⁻ mice on different genetic backgrounds were investigated.
- Find related publications in this database (using NLM MeSH Indexing)
- Acute Disease -
- Animals -
- Chemical and Drug Induced Liver Injury, Chronic - etiology
- Chemical and Drug Induced Liver Injury, Chronic - genetics
- Chemical and Drug Induced Liver Injury, Chronic - pathology
- Disease Models, Animal -
- Fatty Liver - chemically induced
- Fatty Liver - genetics
- Fatty Liver - pathology
- Female -
- Gene Expression - drug effects
- Genetic Predisposition to Disease -
- Keratin-18 - genetics
- Keratin-18 - metabolism
- Keratin-8 - genetics
- Keratin-8 - metabolism
- Liver - drug effects
- Liver - metabolism
- Liver - pathology
- Male -
- Mallory Bodies - drug effects
- Mallory Bodies - metabolism
- Mallory Bodies - pathology
- Mice -
- Mice, Knockout -
- Organ Size -
- Proteins - genetics
- Proteins - metabolism
- Pyridines - toxicity
- Find related publications in this database (Keywords)
- DDC
- intermediate filaments
- keratin deficiency
- sclerosing cholangitis
- steatohepatitis