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Maternal exposure to high level of ursodeoxycholic acid during pregnancy promotes hepatic lipid deposition in the offspring by reducing the methylation level of Fasn gene

Dan Hu,Xiaoting Wu,Manman Hou,Pin Song,Qu Chen,Yingdong Ni

Ursodeoxycholic acid (UDCA) has been widely used for treatment of biliary diseases   with high incidence among pregnant women. However, the effect of maternal UDCA exposure on offspring metabolism particularly on hepatic lipid metabolism has not been reported. Seventeen pregnant Sprague-Dawley rats were administered with low-dosage   UDCA (L-UDCA, 250 mg/kg, n = 6), high-dosage UDCA (H-UDCA, 500 mg/kg, n = 6) or phosphate buffered saline (CON, n = 5) during pregnancy. After parturition, pups from each litter were sacrificed for blood and hepatic tissues sampling at 21 days of age. Maternal exposure to H-UDCA   increased body weight and liver weight of the offspring before weaning. The levels of triglyceride (TG) in both plasma and liver of offspring were increased in maternal UDCA exposure and led to a greater hepatic lipid deposition in offspring. UDCA treatment predominantly promoted the d e novo lipogenesis (DNL) in offspring liver by upregulating the gene expression of ATP citrate lyase ( Acly ), acetyl-coA carboxylases ( Acc ), and fatty acid synthase ( Fasn ), as well as protein expression of FASN and ACC. The level of fibroblast growth factor 15 (FGF15) in plasma of offspring was increased in UDCA treatment compared to control. Moreover, protein expression of DNA methyltransferase 1 (DNMT1) in the liver of offspring was decreased in a dose-dependent manner and the CpG methylation level in the   Fasn   promoter region was decreased. This study provides insights into maternal UDCA exposure promoting offspring hepatic lipid deposition, which is associated with hypomethylation modification of cytosine-phosphate-guanine (CpG) islands on the promoter of   Fasn   gene.