Elevated Levels of Hepatocyte Nuclear Factor 3β in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis

摘要

The winged helix transcription factor, hepatocyte nuclear factor-3β (HNF-3β), mediates the hepatocyte-specific transcription of numerous genes important for liver function. However, the in vivo role of HNF-3β in regulating these genes remains unknown because homozygous null HNF3β mouse embryos die in utero prior to liver formation. In order to examine the regulatory function of HNF-3β, we created transgenic mice in which the ?3-kb transthyretin promoter functions to increase hepatocyte expression of the rat HNF-3β protein. Postnatal transgenic mice exhibit growth retardation, depletion of hepatocyte glycogen storage, and elevated levels of bile acids in serum. The retarded growth phenotype is likely due to a 20-fold increase in hepatic expression of insulin-like growth factor binding protein 1 (IGFBP-1), which results in elevated levels in serum of IGFBP-1 and limits the biological availability of IGFs required for postnatal growth. The defects in glycogen storage and serum bile acids coincide with diminished postnatal expression of hepatocyte genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glycogen synthase) and sinusoidal bile acid uptake (Ntcp), respectively. These changes in gene transcription may result from the disruptive effect of HNF-3β on the hepatic expression of the endogenous mouse HNF-3α,-3β, -3γ, and -6 transcription factors. Furthermore, adult transgenic livers lack expression of the canalicular phospholipid transporter, mdr2, which is consistent with ultrastructure evidence of damage to transgenic hepatocytes and bile canaliculi. These transgenic studies represent the first in vivo demonstration that the HNF-3β transcriptional network regulates expression of hepatocyte-specific genes required for bile acid and glucose homeostasis, as well as postnatal growth.