Increased Fibrosis and Ductular Reaction in Liver of Offspring Exposed to Maternal High Fat Diet

Authors

Michael Thompson (Nationwide Children's Hospital), Mary Cismowski (Nationwide Children's Hospital), Lynette Rogers (Nationwide Children's Hospital), David Brigstock (Nationwide Children's Hospital)

Body

Background: The Developmental Origins of Health and Disease hypothesis states that a poor nutritional environment in utero can increase the risk of developing chronic diseases including non-alcoholic fatty liver disease (NAFLD). Due to the high prevalence of maternal obesity, maternal high fat diet (HFD) is one nutritional exposure of significant concern. Animal models of maternal HFD exposure show that offspring have an increased risk for NAFLD. Whether this impacts disease progression is not clear, but a better understanding could help explain why some patients with NAFLD are prone to develop progressive disease and provide targets for preventative therapy. The goal of the current study was to determine the effect of maternal HFD exposure in utero and during lactation on offspring liver histopathology with a specific focus on fibrosis. Methods: Female C57Bl6 mice were fed a control diet (CD, 10% kcal from fat) or HFD (60% kcal from fat) for 8 weeks and bred with lean males. Dams were continued on the same diet with offspring maintained on either CD or HFD for 12 weeks. Histology, gene, and protein expression analyses of liver from offspring were performed. Results: Offspring exposed to perinatal HFD and then placed on HFD (HFD/HFD) at weaning showed more extensive hepatosteatosis than offspring which were placed on HFD after perinatal CD. Offspring exposed to perinatal HFD and then placed on CD (HFD/CD) for 12 weeks develop steatosis and significant pericellular fibrosis in the liver.  Increased alpha-smooth muscle actin positive stellate cells and cytokeratin-19/beta-catenin positive ductular reaction are present throughout the liver parenchyma in HFD/CD offspring.  HFD/CD offspring liver also exhibit significant hepatocyte proliferation despite overall liver weight being smaller.  No difference in F4/80 positive macrophages was observed between each group. Conclusions: Perinatal HFD exposure induces pathologic changes in liver of offspring that persist into adulthood and impact the response to dietary exposure including worsening steatosis and fibrosis. This indicates that exposure to perinatal HFD promotes more rapid disease progression of NAFLD in the adult offspring with a sustained fibrotic phenotype and ductular reaction even in the absence of post-natal HFD exposure. Support or Funding InformationNationwide Children's Hospital Research Institute

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