title: Insulin resistance and metabolic hepatocarcinogenesis with parent-of-origin effects in A×B mice.
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.
authors.affiliation: Department of Nutrition Sciences, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Hines
authors.forename: Hadley J
authors.initials: HJ
authors.lastname: Hartwell
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Theve
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hall
authors.forename: Sara
authors.initials: S
authors.lastname: Hashway
authors.forename: Jessica
authors.initials: J
authors.lastname: Connolly
authors.forename: Michelle
authors.initials: M
authors.lastname: Fecteau
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
mesh_terms: D017667:Adipocytes / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004843:Epistasis, Genetic / Q000235:genetics*; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D022781:Hepatocytes / Q000473:pathology; D006946:Hyperinsulinism / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D016207:Cytokines