Differential expression of lipid metabolic genes in hypercholesterolemic rabbit placenta predisposes the offspring to develop atherosclerosis in early adulthood

Aims: Maternal hypercholesterolemia (MHC) is a pathological condition that may cause atherosclerosis in the adulthood of the offspring. The study aims to identify the role of in-utero programming by the placenta in atherogenesis and associated liver pathology in offspring.Main methods: Female New Zealand white rabbits with normal lipid profiles were fed a 0.3 % HFD after mating. Lipid levels were monitored, and pregnant rabbits were sacrificed at the end of trimester 1, trimester 2, and trimester 3. Placental histology and expression of lipid metabolism genes were studied. Lipid levels, aortic lesions, and mRNA expression of cholesterol synthesis genes were investigated in fetuses at the end of gestation. A group of fetuses was allowed to attain early adulthood to investigate the liver lipid metabolism and atherogenesis with and without an HFD.Key findings: Elevated maternal lipid levels and placental gene expression were differentially modulated in HFDfed mothers. HFD-fed rabbits demonstrated differential expression of the placental genes involved in receptormediated endocytosis of cholesterol, lipogenesis, and lipolysis in all three trimesters. It resulted in significant lipid depositions in the placenta, hyperlipidemia, and a decrease in hepatic cholesterol synthesis in fetuses at the end of gestation. There was no atherogenesis in the aorta of offspring at trimester 3, but such offspring of HFDfed mothers developed atherosclerosis and non-alcoholic fatty liver (NAFL) with profound steatosis in their early adulthood with and without HFD.Significance: Diet-induced MHC differentially expressed placental lipid genes that may program the offspring to develop atherosclerosis and associated NAFL in early adulthood.

Automated summary

Maternal hypercholesterolemia can lead to atherosclerosis in the offspring. This study investigates the role of placenta in atherogenesis and associated liver pathology. The findings suggest that a high-fat diet results in increased placental lipid deposition, fetal hyperlipidemia, and the development of atherosclerosis and non-alcoholic fatty liver in early adulthood.