Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice
Name
AJP11-0112T_RevisedwFigs.pdf
Description
Hines - lead author
Size
7.93 MB
Format
Adobe PDF
Checksum (MD5)
098d514a4ef95b2611373c8324820439
Author(s)
Hines, Ian N.
Hartwell, Hadley J.
Feng, Yan
Theve, Elizabeth J
Hall, Gregory
Hashway, Sara A.
Connolly, Jessica
Fecteau, Michelle
Fox, James G
Rogers, Arlin B.
Date Issued
October 2011
Journal
American Journal of Pathology
Publisher
Elsevier
Citation
Hines, Ian N., Hadley J. Hartwell, Yan Feng, Elizabeth J. Theve, Gregory A. Hall, Sara Hashway, Jessica Connolly, Michelle Fecteau, James G. Fox, and Arlin B. Rogers. “Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice.” The American Journal of Pathology 179, no. 6 (December 2011): 2855-2865.
Version
Author's final manuscript
Abstract
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 AB6F1 (A/JCr dam × C57BL/6 sire) but not B6AF1 (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 autosomal 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 products. 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.
MIT Department
Massachusetts Institute of Technology. Division of Comparative Medicine
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.ajpath.2011.08.014
