Figure 6
From: A maternal high-fat diet induces fetal origins of NASH-HCC in mice
Maternal HFD consumption induced hepatomegaly without a compensatory increase in blood flow in fetuses. (A) Phase-contrast micro-CT images of fetuses (upper panels) were uploaded to advanced 3D image processing and quantification software (Amira, version 1.4.0, https://www.thermofisher.com) and 3D images of the fetal liver and intrahepatic vascular structure (lower panels) are presented. (B) Liver volume of fetuses (VLiver). The volume of the extracted liver was derived by forming multiple tetrahedrons with the center point as the apex in Amira. CD; n = 4, HFD; n = 6. (C) Hepatic vessels were extracted from fetuses using 3D image processing and quantification software (Amira). Intrahepatic blood vessels were extracted from the umbilical vein (yellow arrowhead) just before they entered the liver and branched. The blood flow rate was determined by deriving the vessel diameter, which is proportional to the multiplier of the vessel diameter according to Murray’s law (left panel). An open-source toolkit (Vascular Modelling Toolkit, version 1.4.0, VMTK, www.vmtk.org) was used to derive the vessel diameter semiautomatically (right panel). (D) Diameter of the umbilical vein (DUV) of fetuses. CD; n = 4, HFD; n = 6. (E) The blood flow rate is proportional to DUV3 per volume of fetal liver (VLiver). CD; n = 4, HFD; n = 6. All measured variables were log(e) transformed for statistical analysis. The significance of the differences between groups was determined using unpaired Student’s t tests. *p < 0.05 and **p < 0.01. (F) Maternal HFD consumption induces hepatomegaly without increasing hepatic blood flow in the fetus, resulting in hypoxia in the fetal liver. Hypoxia induces nonmitochondrial ROS production, leading to the upregulation of HORMAD1 in the fetal liver. After birth, breathing induced normoxia in the livers of offspring, attenuating the increased HORMAD1 expression. Obesity, diabetes and aging, which are known to induce hypoxia and ROS production, might increase HORMAD1 expression. The first hit in NAFLD/NASH/HCC development might be that fetal nutrition causes hepatic hypoxia. Thus, HORMAD1 expression is an indicator of tissue hypoxia resulting from ROS production.
