Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis

Tan, T.C.H., Crawford, D.H.G., Jaskowski, L.A., Murphy, T.M., Heritage, M.L., Subramaniam, V.N., Clouston, A.D., Anderson, G.J., & Fletcher, L.M. (2011) Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis. American Journal of Physiology, 301(5), G865-G876.

View at publisher

Abstract

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-α 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 β-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.

Impact and interest:

16 citations in Scopus
Search Google Scholar™
16 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 99842
Item Type: Journal Article
Refereed: Yes
DOI: 10.1152/ajpgi.00150.2011
ISSN: 0002-9513
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Deposited On: 14 Oct 2016 01:15
Last Modified: 17 Oct 2016 04:23

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page