Altered Lipid Metabolism in Hfe-Knockout Mice Promotes Severe NAFLD and Early Fibrosis

Tan, Terrence C.H., Crawford, Darrell H.G., Jaskowski, Lesley A., Murphy, Therese M., Heritage, Mandy L., Subramaniam, V. Nathan, Clouston, Andrew D., Anderson, Gregory J. and Fletcher, Linda M. (2011) Altered Lipid Metabolism in Hfe-Knockout Mice Promotes Severe NAFLD and Early Fibrosis. American Journal of Physiology: Gastrointestinal and Liver Physiology, 301 5: 1-39. doi:10.1152/ajpgi.00150.2011

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Author Tan, Terrence C.H.
Crawford, Darrell H.G.
Jaskowski, Lesley A.
Murphy, Therese M.
Heritage, Mandy L.
Subramaniam, V. Nathan
Clouston, Andrew D.
Anderson, Gregory J.
Fletcher, Linda M.
Title Altered Lipid Metabolism in Hfe-Knockout Mice Promotes Severe NAFLD and Early Fibrosis
Journal name American Journal of Physiology: Gastrointestinal and Liver Physiology   Check publisher's open access policy
ISSN 0193-1857
Publication date 2011-01-01
Year available 2011
Sub-type Article (original research)
DOI 10.1152/ajpgi.00150.2011
Open Access Status Not yet assessed
Volume 301
Issue 5
Start page 1
End page 39
Total pages 39
Place of publication Bethesda, MD, U.S.A.
Publisher American Physiological Society
Language eng
Subject 1314 Physiology
2721 Hepatology
2715 Gastroenterology
2737 Physiology (medical)
Abstract Tan TC, Crawford DH, Jaskowski LA, Murphy TM, Heritage ML, Subramaniam VN, Clouston AD, Anderson GJ, Fletcher LM. Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis. Am J Physiol Gastrointest Liver Physiol 301: G865-G876, 2011. First published August 4, 2011; doi:10.1152/ajpgi.00150.2011.-The HFE protein plays a crucial role in the control of cellular iron homeostasis. Steatosis is commonly observed in HFE-related iron-overload disorders, and current evidence suggests a causal link between iron and steatosis. Here, we investigated the potential contribution of HFE mutations to hepatic lipid metabolism and its role in the pathogenesis of nonalcoholic fatty liver disease. Wild-type (WT) and Hfe knockout mice (Hfe(-/-)) were fed either standard chow, a monounsaturated low fat, or a high-fat, high-carbohydrate diet (HFD) and assessed for liver injury, body iron status, and markers of lipid metabolism. Despite hepatic iron concentrations and body weights similar to WT controls, Hfe(-/-) mice fed the HFD developed severe hypoxia-related steatohepatitis, Tnf-alpha activation, and mitochondrial respiratory complex and antioxidant dysfunction with early fibrogenesis. These features were associated with an upregulation in the expression of genes involved in intracellular lipid synthesis and trafficking, while transcripts for mitochondrial fatty acid beta-oxidation and adiponectin signaling-related genes were significantly attenuated. In contrast, HFD-fed WT mice developed bland steatosis only, with no inflammation or fibrosis and no upregulation of lipogenesis-related genes. A HFD led to reduced hepatic iron in Hfe(-/-) mice compared with chow-fed mice, despite higher serum iron, decreased hepcidin expression, and increased duodenal ferroportin mRNA. In conclusion, our results demonstrate that Hfe(-/-) mice show defective hepatic-intestinal iron and lipid signaling, which predispose them toward diet-induced hepatic lipotoxicity, accompanied by an accelerated progression of injury to fibrosis.
Keyword Gastroenterology & Hepatology
Gastroenterology & Hepatology
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article in press, published online August 4 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
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Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 22 Sep 2011, 19:14:34 EST by Matthew Lamb on behalf of School of Medicine