Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle

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Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle. / Dowman, Joanna K; Hopkins, Laurence J; Reynolds, Gary M; Nikolaou, Nikolaos; Armstrong, Matthew J; Shaw, Jean C; Houlihan, Diarmaid D; Lalor, Patricia F; Tomlinson, Jeremy W; Hübscher, Stefan G; Newsome, Philip N.

In: The American Journal of Pathology, Vol. 184, No. 5, 05.2014, p. 1550-61.

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@article{230a8a6a272b4a5d85b22e32e08bc8d8,
title = "Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle",
abstract = "Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.",
keywords = "Animals, Carcinoma, Hepatocellular, Diet, High-Fat, Disease Models, Animal, Fructose, Gene Expression Regulation, Humans, Insulin, Lipid Metabolism, Liver, Liver Neoplasms, Male, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease, Obesity, SOX9 Transcription Factor, Sedentary Lifestyle, Signal Transduction, Stem Cells",
author = "Dowman, {Joanna K} and Hopkins, {Laurence J} and Reynolds, {Gary M} and Nikolaos Nikolaou and Armstrong, {Matthew J} and Shaw, {Jean C} and Houlihan, {Diarmaid D} and Lalor, {Patricia F} and Tomlinson, {Jeremy W} and H{\"u}bscher, {Stefan G} and Newsome, {Philip N}",
note = "Copyright {\textcopyright} 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.",
year = "2014",
month = may,
doi = "10.1016/j.ajpath.2014.01.034",
language = "English",
volume = "184",
pages = "1550--61",
journal = "The American Journal of Pathology",
issn = "0002-9440",
publisher = "American Society for Investigative Pathology",
number = "5",

}

RIS

TY - JOUR

T1 - Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle

AU - Dowman, Joanna K

AU - Hopkins, Laurence J

AU - Reynolds, Gary M

AU - Nikolaou, Nikolaos

AU - Armstrong, Matthew J

AU - Shaw, Jean C

AU - Houlihan, Diarmaid D

AU - Lalor, Patricia F

AU - Tomlinson, Jeremy W

AU - Hübscher, Stefan G

AU - Newsome, Philip N

N1 - Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PY - 2014/5

Y1 - 2014/5

N2 - Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.

AB - Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.

KW - Animals

KW - Carcinoma, Hepatocellular

KW - Diet, High-Fat

KW - Disease Models, Animal

KW - Fructose

KW - Gene Expression Regulation

KW - Humans

KW - Insulin

KW - Lipid Metabolism

KW - Liver

KW - Liver Neoplasms

KW - Male

KW - Mice, Inbred C57BL

KW - Non-alcoholic Fatty Liver Disease

KW - Obesity

KW - SOX9 Transcription Factor

KW - Sedentary Lifestyle

KW - Signal Transduction

KW - Stem Cells

U2 - 10.1016/j.ajpath.2014.01.034

DO - 10.1016/j.ajpath.2014.01.034

M3 - Article

C2 - 24650559

VL - 184

SP - 1550

EP - 1561

JO - The American Journal of Pathology

JF - The American Journal of Pathology

SN - 0002-9440

IS - 5

ER -