Genetic background effects of keratin 8 and 18 in a DDC-induced hepatotoxicity and Mallory-Denk body formation mouse model

被引：33

作者：

Haybaeck, Johannes ^{[1
]}

Stumptner, Cornelia ^{[1
]}

Thueringer, Andrea ^{[1
]}

Kolbe, Thomas ^{[2
,3
]}

Magin, Thomas M. ^{[4
]}

Hesse, Michael ^{[5
]}

Fickert, Peter ^{[6
]}

Tsybrovskyy, Oleksiy ^{[1
]}

Mueller, Heimo ^{[1
]}

Trauner, Michael ^{[6
,7
]}

Zatloukal, Kurt ^{[1
]}

Denk, Helmut ^{[1
]}

机构：

[1] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[2] Univ Vet Med Vienna, Vienna, Austria

[3] Univ Nat Resources & Appl Life Sci, IFA Tulln, Vienna, Austria

[4] Univ Leipzig, Inst Biol, Translat Ctr Regenerat Med Leipzig, Leipzig, Germany

[5] Univ Bonn, Inst Biochem & Mol Biol, Div Cell Biochem, Bonn, Germany

[6] Med Univ Graz, Lab Expt & Mol Hepatol, Dept Internal Med, Div Gastroenterol & Hepatol, Graz, Austria

[7] Med Univ Vienna, Dept Med 3, Div Gastroenterol & Hepatol, Vienna, Austria

来源：

LABORATORY INVESTIGATION | 2012年 / 92卷 / 06期

基金：

奥地利科学基金会;

关键词：

DDC; intermediate filaments; keratin deficiency; sclerosing cholangitis; steatohepatitis; INTERMEDIATE-FILAMENTS; MULTIPLE SITES; LIVER; OSTEOPONTIN; MICE; PHOSPHORYLATION; SUSCEPTIBILITY; DISEASE; BODIES; OVEREXPRESSION;

D O I：

10.1038/labinvest.2012.49

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

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. Laboratory Investigation (2012) 92, 857-867; doi:10.1038/labinvest.2012.49; published online 26 March 2012

引用

页码：857 / 867

页数：11

共 47 条

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MIDGESTATIONAL LETHALITY IN MICE LACKING KERATIN-8 [J].