Elevated levels of hepatocyte nuclear factor 3beta in mouse hepatocytes influence expression of genes involved in bile acid and glucose homeostasis.
The winged helix transcription factor, hepatocyte nuclear factor-3beta (HNF-3beta), mediates the hepatocyte-specific transcription of numerous genes important for liver function. However, the in vivo role of HNF-3beta in regulating these genes remains unknown because homozygous null HNF3beta mouse embryos die in utero prior to liver formation. In order to examine the regulatory function of HNF-3beta, we created transgenic mice in which the -3-kb transthyretin promoter functions to increase hepatocyte expression of the rat HNF-3beta 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-3beta on the hepatic expression of the endogenous mouse HNF-3alpha,-3beta, -3gamma, 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-3beta transcriptional network regulates expression of hepatocyte-specific genes required for bile acid and glucose homeostasis, as well as postnatal growth.
Rausa
F M
FM
Departments of Molecular Genetics, Medicine, Physiology, and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607-7170, USA.
Tan
Y
Y
Zhou
H
H
Yoo
K W
KW
Stolz
D B
DB
Watkins
S C
SC
Franks
R R
RR
Unterman
T G
TG
Costa
R H
RH
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent; D010641:Phenotype; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism; D027981:Symporters; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C496503:Foxa2 protein, mouse; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D008024:Ligands; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; C496606:Onecut1 protein, mouse; D029363:Organic Anion Transporters, Sodium-Dependent; D011228:Prealbumin; D020033:Protein Isoforms; D011994:Recombinant Proteins; D027981:Symporters; D015534:Trans-Activators; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; C071908:sodium-bile acid cotransporter; D006003:Glycogen; C095122:multidrug resistance protein 3; D005982:Glutathione Transferase; D005947:Glucose