| Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice. | |
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MedLine Citation:
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PMID: 21967816 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Insulin resistance is a defining feature of metabolic syndrome and type 2 diabetes mellitus but also may occur independently of these conditions. Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of these disorders, increases the risk of hepatocellular carcinoma (HCC). However, mechanisms linking hyperinsulinemia to NAFLD and HCC require clarification. We describe a novel model of primary insulin resistance and HCC with strong parent-of-origin effects. Male AB6 F(1) (A/JCr dam × C57BL/6 sire) but not B6A F(1) (B6 dam × A/J sire) mice developed spontaneous insulin resistance, NAFLD, and HCC without obesity or diabetes. A survey of mitochondrial, imprinted, and sex-linked traits revealed modest associations with X-linked genes. However, a diet-induced obesity study, including B6.A chromosome substitution-strain (consomic) mice, showed no segregation by sex chromosome. Thus, parent-of-origin effects were specified within the somatic genome. Next, we interrogated mechanisms of insulin-associated hepatocarcinogenesis. Steatotic hepatocytes exhibited adipogenic transition characterized by vacuolar metaplasia and up-regulation of vimentin, adipsin, fatty acid translocase (CD36), peroxisome proliferator-activated receptor-γ, and related genes. This profile was largely recapitulated in insulin-supplemented primary mouse hepatocyte cultures. Importantly, pyruvate kinase M2, a fetal anabolic enzyme implicated in the Warburg effect, was activated by insulin in vivo and in vitro. Thus, our study reveals parent-of-origin effects in heritable insulin resistance, implicating adipogenic transition with acquired anabolic metabolism in the progression from NAFLD to HCC. |
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Authors:
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Ian N Hines; Hadley J Hartwell; Yan Feng; Elizabeth J Theve; Gregory A Hall; Sara Hashway; Jessica Connolly; Michelle Fecteau; James G Fox; Arlin B Rogers |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-30 |
Journal Detail:
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Title: The American journal of pathology Volume: - ISSN: 1525-2191 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-10-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Nutrition Sciences, East Carolina University, Greenville, North Carolina. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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