Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload.
Iron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure.



Iron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet.



KO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-κB, along with reappearance of β-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-κB and reappearance of β-catenin.



The absence of hepatic β-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders.



Lack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the β-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model.
Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States; Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States.
Morgan E
ME
Preziosi
Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States; Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States.
Sucha
S
Singh
Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States; Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States.
Erika V
EV
Valore
Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States; Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States.
Grace
G
Jung
Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States.
Branimir
B
Popovic
Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States; Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States.
Minakshi
M
Poddar
Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States; Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States.
Shanmugam
S
Nagarajan
Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States; Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States.
Tomas
T
Ganz
Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States; Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States; Department of Medicine (Division of Gastroenterology, Hepatology and Nutrition), University of Pittsburgh, Pennsylvania, United States. Electronic address: smonga@pitt.edu.
Satdarshan P
SP
Monga
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D006432:Hemochromatosis / Q000150:complications / Q000378:metabolism; D006801:Humans; D019190:Iron Overload / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D015398:Signal Transduction; D051176:beta Catenin / Q000172:deficiency* / Q000235:genetics
D000975:Antioxidants; C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D000111:Acetylcysteine
Cytochrome P-450 CYP2E1; Hemochromatosis; Knockout; Lipid peroxidation; Mice; NF-kappa B; Oxidative stress; Wnt signaling