Abstract
The inactivation of the Hnf1beta gene identified an essential role in epithelial differentiation of the visceral endoderm and resulted in early embryonic death. In the present study, we have specifically inactivated this gene in hepatocytes and bile duct cells using the Cre/loxP system. Mutant animals exhibited severe jaundice caused by abnormalities of the gallbladder and intrahepatic bile ducts (IHBD). The paucity of small IHBD was linked to a failure in the organization of duct structures during liver organogenesis, suggesting an essential function of Hnf1b in bile duct morphogenesis. Mutant mice also lacked interlobular arteries. As HNF1beta is not expressed in these cells, it further emphasizes the link between arterial and biliary formation. Hepatocyte metabolism was also affected and we identified hepatocyte-specific HNF1beta target genes involved in bile acids sensing and in fatty acid oxidation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyl-CoA Dehydrogenase, Long-Chain
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Alleles
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Bile Acids and Salts / metabolism
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Bile Ducts / abnormalities
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Bile Ducts / embryology*
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Bile Ducts, Intrahepatic / abnormalities
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Bile Ducts, Intrahepatic / embryology
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Bilirubin / metabolism
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Cholesterol / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Epithelial Cells
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Fatty Acid Desaturases / genetics
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Gallbladder / abnormalities
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Gallbladder / embryology
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Gene Targeting
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Hepatocyte Nuclear Factor 1-beta
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Jaundice
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Lipid Metabolism
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Liver / physiopathology*
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Morphogenesis
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Mutagenesis
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Organic Anion Transporters, Sodium-Independent / genetics
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Triglycerides / metabolism
Substances
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Bile Acids and Salts
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DNA-Binding Proteins
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Organic Anion Transporters, Sodium-Independent
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Slco1a1 protein, rat
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Transcription Factors
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Triglycerides
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Hepatocyte Nuclear Factor 1-beta
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Cholesterol
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Fatty Acid Desaturases
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Acyl-CoA Dehydrogenase, Long-Chain
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Bilirubin