Keratin 18-deficiency results in steatohepatitis and liver tumors in old mice: A model of steatohepatitis-associated liver carcinogenesis.

Kira Bettermann,Andrea Thüringer,Eva M Hofer,Cornelia Stumptner,Johannes Haybaeck,Helmut Denk,Michael G Schimek,Michael R Speicher,Christina Wohlrab,Nicole Golob-Schwarzl,Vendula Svendova,Carolin Lackner,Anita Kuldeep Mehta,Kurt Zatloukal

doi:10.18632/oncotarget.12325

Abstract

BackroundSteatohepatitis (SH)-associated liver carcinogenesis is an increasingly important issue in clinical medicine. SH is morphologically characterized by steatosis, hepatocyte injury, ballooning, hepatocytic cytoplasmic inclusions termed Mallory-Denk bodies (MDBs), inflammation and fibrosis.Results17-20-months-old Krt18−/− and Krt18+/− mice in contrast to wt mice spontaneously developed liver lesions closely resembling the morphological spectrum of human SH as well as liver tumors. The pathologic alterations were more pronounced in Krt18−/− than in Krt18+/− mice. The frequency of liver tumors with male predominance was significantly higher in Krt18−/− compared to age-matched Krt18+/− and wt mice. Krt18-deficient tumors in contrast to wt animals displayed SH features and often pleomorphic morphology. aCGH analysis of tumors revealed chromosomal aberrations in Krt18−/− liver tumors, affecting loci of oncogenes and tumor suppressor genes.Materials and MethodsLivers of 3-, 6-, 12- and 17-20-months-old aged wild type (wt), Krt18+/− and Krt18−/− (129P2/OlaHsd background) mice were analyzed by light and immunofluorescence microscopy as well as immunohistochemistry. Liver tumors arising in aged mice were analyzed by array comparative genomic hybridization (aCGH).ConclusionsOur findings show that K18 deficiency of hepatocytes leads to steatosis, increasing with age, and finally to SH. K18 deficiency and age promote liver tumor development in mice, frequently on the basis of chromosomal instability, resembling human HCC with stemness features.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem affecting one third of the adult population in developed countries [1]
Our findings show that K18 deficiency of hepatocytes leads to steatosis, increasing with age, and to SH
non-alcoholic steatohepatitis (NASH) is characterized by steatosis, inflammation and hepatocyte injury, morphologically expressed by ballooning and Mallory-Denk body (MDB) formation, leading to fibrosis and cirrhosis [2]

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem affecting one third of the adult population in developed countries [1]. E.g., diet rich in saturated fats, central obesity and sedentary behavior, increases the risk of the development of fatty liver with eventual progression to non-alcoholic steatohepatitis (NASH). NASH is characterized by steatosis, inflammation and hepatocyte injury, morphologically expressed by ballooning and Mallory-Denk body (MDB) formation, leading to fibrosis and cirrhosis [2]. In this setting, HCC may closely recapitulate the morphologic picture of steatohepatitis (SH) in non-neoplastic liver [3]. NASH represents an important etiology of hepatocellular carcinoma (HCC), sometimes even in the absence of cirrhosis [3]

Methods

Results

Conclusion