Gene expression of the three members of hepatocyte nuclear factor-3 is differentially regulated by nutritional and hormonal factors

Hepatocyte nuclear factor-3 (HNF-3) belongs to a large family of forkhead transcription factors and is made up of three members (HNF-3 alpha, -3 beta and -3 gamma). It has been shown that HNF-3 regulates a number of metabolically important genes. However, the mechanisms underlying this regulation of HNF-3 activity by hormones and nutrition have not yet been well elucidated. In attempting to explore the regulation of gene expression of HNF-3 members by physiological status, we analyzed the effects of insulin. dexamethasone and protein malnutrition on the hepatic mRNA level of each member. Male Wistar rats were fed on a 12% casein diet, 12% gluten diet (deficient in lysine and threonine) or a protein-free diet for 1 week. The protein-free diet and gluten diet caused a 3.7-fold increase in HNF-3 gamma mRNA in the liver and did not affect the mRNA level of either HNF-3 alpha or HNF-3 beta. Daily administration of dexamethasone caused the mRNA levels of HNF-3 alpha and HNF-3 beta to increase (2.3- and 1.4-fold, respectively), but had no effect on the HNF-3 gamma mRNA level. In diabetic rats that had been injected with streptozotocin, an elevation of the hepatic mRNA levels of HNF-3 beta and HNF-3 gamma was observed (1.6-and 1.9-fold, respectively). Insulin replacement in the diabetic rats decreased both mRNA levels in a dose-dependent manner. HNF-3 alpha mRNA was not affected by insulin status. These results show that the genes of the three members of the HNF-3 family respond differently to hormonal and nutritional factors suggesting that the activities of HNF-3 members an regulated, at least in part, by the levels of their gene expression.