Establishment of a Mouse Model of Glucocorticoid Receptor Gene Knockout in Fetal Liver and its Application in Related Fetal-Originated Diseases

The basic level of glucocorticoids in utero is not only the key to regulate the morphology and functional maturity of fetal tissue (including liver), but also the cause of various fetal-originated diseases. Glucocorticoid functions mainly through the glucocorticoid receptor (GR, encoded by NR3C1). However, the effect of fetal liver NR3C1 knockout on fetal-originated diseases has not been reported to date. In this study, we first obtained liver-specific Nr3c1 knockout (Nr3c1-LKO) mice by hybridizing Nr3c1 flox/flox mice with ALB-Cre transgenic mice. Then, PCR and Western blot were used to verify the phenotype. The expression of the hepatic Nr3c1 mRNA, GR protein, and several downstream target genes (such as Tsc22d3, Sgk1, Tat and Mt1) in Nr3c1-LKO mice were found significantly decreased prenatally and postnatally. The survival rate of newborns was 79.4% within 200 min after birth. Furthermore, we found that Nr3c1-LKO mice had reduced birth weight, liver weight and serum glucose levels, and decreased number of liver cells, vacuolated cytoplasm, decreased Igf1 expression, gluconeogenesis and glycogen synthesis, and enhanced glucose transport and triglyceride synthesis. The above changes persisted postnatally, and the liver cholesterol synthesis function was enhanced, reversal function was weakened, associated with hyperlipidemia. In conclusion, we successfully constructed the fetal Nr3c1-LKO mice, confirming the role of fetal GR in physiological regulation of glucose and lipid metabolism and susceptibility to related fetal-originated diseases (such as fatty liver and hypercholesterolemia) in offspring. It also provides technical support for further understanding the developmental origin and programming mechanism of various fetal-originated diseases.