Feeding pregnant rats a low-protein diet alters the hepatic expression of SREBP-1c in their offspring via a glucocorticoid-related mechanism

Prenatal exposure to a low-protein diet programmes altered expression of genes that regulate lipid metabolism, including SREBP-1c. The main aim of this study was to investigate whether programmed changes to hepatic SREBP-1c expression in the rat are glucocorticoid-dependent. Rats were fed isocaloric diets (control or low-protein) throughout pregnancy. The low-protein group received 11 beta-hydroxylase inhibitor, the inhibitor plus corticosterone, or vehicle injections over the first 2 weeks of pregnancy. The control group was administered vehicle injections only. On delivery the animals were transferred to a standard chow diet. The offspring were weaned at 4 weeks of age on to the same chow diet and killed for collection of liver tissue. The inhibitor of glucocorticoid synthesis reversed the suppressive effect of low-protein diet on hepatic SREBP-1c expression of both protein and mRNA seen in low-protein exposed offspring. To test if this effect is through direct effect on the SREBP-1c promoter, H4IIE cells were transfected with a luciferase reporter construct controlled by the SREBP-1c promoter treated with dexamethasone. Dexamethasone induced the expression of SREBP-1c in vitro. Together these studies demonstrate that foetal over-exposure to glucocorticoids, through indirect mechanism, play a crucial role in low-protein-diet-induced changes in lipid metabolism regulating genes.