Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), is associated with hepatocellular carcinoma (HCC). The worldwide prevalence of NAFLD in children suggests an early-life origin. To examine the impact of intrauterine nutrition on the development of NASH/HCC, female C57BL/6J mice were fed with either high-fat diet (HFD) or control diet (CD) during gestation. After weaning, the male offspring were fed with CD, generating two groups of male offspring, HFD and CD. HFD remarkably elevated plasma NEFA and ALT. Consistently, HFD had severe form of NASH, presenting the fibrosis, accompanied with HCC. Synchrotron micro-CT showed the architectural remodeling of the parenchyma in HFD at 14.5 days postcoitum (dpc), one week and 15 weeks of age, not in CD. In the liver of HFD at 14.5dpc, gene ontology term enrichment analysis suggested that up-regulated differentially expressed genes (DEGs) significantly enriched in DNA alkylation, bile secretion, and the down-regulated DEGs mainly enriched in neuronal system, cell maturation. KEGG pathway analysis found down-regulated DEGs significantly enriched in five pathways including Graft-versus-host disease (LogP -24.785) such as FasL, and up-regulated HIF-1 signaling pathway in the liver of HFD at one week of age. On the contrary, 15-week-old HFD had increased cytoplasmic pimonidazole staining, but no nuclear staining of HIF-1α in HCC cells, which suggests breakdown of hypoxic response mechanism, concomitantly with up-regulated miR199a-5p, miR-1949, miR214-3p and miR-3090-5p, which target HIF-1α. This study demonstrates that the early exposure to an overnutrition in utero, subsequent neonatal and adult nutritional alternation cause NASH/HCC in offspring, accompanied by multiple changes in gene expressions. This means a “multi-hit theory.”


T. Takiyama: None. R. Bessho: None. K. Sawamoto: None. Y. Takiyama: Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Roche Diagnostics K.K., Taisho Pharmaceutical Co., Ltd.

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