![]() The younger age of onset of NASH suggests an increasing effect of the prenatal nutritional environment. Actually, the incidence of liver transplantations for NASH cirrhosis in individuals aged 18 to 40 years in the US increased from 0.53% in 2002 to 4.46% in 2012, indicating an annual increase rate of 14% per year in liver transplant indications for NASH 13. Because 20% of patients with NASH will develop cirrhosis, NASH will become the leading indication for liver transplantation in the US 12. In particular, approximately half of all NAFLD cases in children have progressed to NASH by the time of diagnosis 11. ![]() NASH, the most advanced form of NAFLD, has a high risk of progressing to cirrhosis and hepatocellular carcinoma and is becoming a major cause of end-stage liver disease. Currently, one in four members of the adult population worldwide is affected by NAFLD. NAFLD affects 70–80% of patients with type 2 diabetes and 30–40% of adults with type 1 diabetes 9, 10. ![]() Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease 8. Therefore, studies examining the metabolic abnormalities that overnutrition during fetal life may cause in adulthood are urgently needed. In addition, maternal obesity is associated with placental hypoxia and may increase the risk of severe fetal and neonatal complications 7. ![]() Fetal hypoxia has also been suggested to cause increased erythropoiesis on the first day after birth in infants of mothers with diabetes 6. A previous cohort study reported increased erythropoietin levels in cord blood with an increase in the maternal body mass index without differences in placental lesions, likely as a result of chronic fetal hypoxia 5. Fetal exposure to maternal diabetes and hyperglycemia may contribute considerably to the global diabetes epidemic. Currently, 50% of women of reproductive age are obese 3, and one in seven women has gestational diabetes at birth 4, which is affected by maternal hyperglycemia. Support for this pathogenetic mechanism comes from epidemiological studies of low-birth-weight infants during wartime 2. The prenatal environment is a nongenetic factor that leads to epigenetic changes in early development 1. Based on these findings, a maternal HFD induces fetal origins of NASH/HCC via hypoxia, and HORMAD1 is a potential therapeutic target for NASH/HCC. Synchrotron-based phase-contrast micro-CT of the fetuses from HFD-fed dams showed significant enlargement of the liver accompanied by a consistent size of the umbilical vein, which may cause hypoxia in the fetal liver. In contrast, N-acetylcysteine, but not rotenone, inhibited hypoxia-induced Hormad1 expression, indicating its dependency on nonmitochondrial reactive oxygen species production. Despite the presence of three putative hypoxia response elements within the mouse Hormad1 gene, the Hif-1alpha siRNA only slightly decreased hypoxia-induced Hormad1 mRNA expression. Hypoxia substantially increased Hormad1 expression in primary mouse hepatocytes. The cancer/testis antigen HORMA domain containing protein 1 (HORMAD1), one of 146 upregulated differentially expressed genes in fetal livers from HFD-fed dams, was overexpressed with hypoxia-inducible factor 1 alpha (HIF-1alpha) in hepatoblasts and in NASH-based hepatocellular carcinoma (HCC) in offspring from HFD-fed dams at 15 weeks old. Male offspring from high-fat diet (HFD)-fed dams developed a severe form of NASH, leading to highly vascular tumor formation. Maternal overnutrition affects offspring susceptibility to nonalcoholic steatohepatitis (NASH). ![]()
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