Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice
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, mec...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/104359 https://orcid.org/0000-0001-9307-6116 |
| _version_ | 1826188531753549824 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Division of Comparative Medicine |
| author_facet | Massachusetts Institute of Technology. Division of Comparative Medicine 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. |
| author_sort | Hines, Ian N. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:01:05Z |
| format | Article |
| id | mit-1721.1/104359 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:01:05Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1043592022-09-23T10:21:16Z Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice 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. Massachusetts Institute of Technology. Division of Comparative Medicine Fox, James G Feng, Yan Theve, Elizabeth J Hall, Gregory Hashway, Sara A. Connolly, Jessica Fecteau, Michelle Fox, James G 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. National Institutes of Health (U.S.) (NIH grant AA016563) National Institutes of Health (U.S.) (NIH grant CA067529) National Institutes of Health (U.S.) (NIH grant P01CA0267) National Institutes of Health (U.S.) (NIH grant P30ES02109) National Institutes of Health (U.S.) (NIH grant RR007036) National Institutes of Health (U.S.) (NIH grant CA158661) National Institutes of Health (U.S.) (NIH grant CA016086) 2016-09-21T18:50:46Z 2016-09-21T18:50:46Z 2011-10 2011-08 Article http://purl.org/eprint/type/JournalArticle 00029440 http://hdl.handle.net/1721.1/104359 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. https://orcid.org/0000-0001-9307-6116 en_US http://dx.doi.org/10.1016/j.ajpath.2011.08.014 American Journal of Pathology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Prof. Fox via Howard Silver |
| spellingShingle | 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. Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice |
| title | Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice |
| title_full | Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice |
| title_fullStr | Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice |
| title_full_unstemmed | Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice |
| title_short | Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice |
| title_sort | insulin resistance and metabolic hepatocarcinogenesis with parent of origin effects in a b mice |
| url | http://hdl.handle.net/1721.1/104359 https://orcid.org/0000-0001-9307-6116 |
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