Disruption of hepatic C/EBPalpha results in impaired glucose tolerance and age-dependent hepatosteatosis.
C/EBPalpha is highly expressed in liver and regulates many genes that are preferentially expressed in liver. Because C/EBPalpha-null mice die soon after birth, it is impossible to analyze the function of C/EBPalpha in the adult with this model. To address the function of C/EBPalpha in adult hepatocytes, liver-specific C/EBPalpha-null mice were produced using a floxed C/EBPalpha allele and the albumin-Cre transgene. Unlike whole body C/EBPalpha-null mice, mice lacking hepatic C/EBPalpha expression did not exhibit hypoglycemia, nor did they show reduced hepatic glycogen in adult. Expression of liver glycogen synthase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase remained at normal levels. However, these mice exhibited impaired glucose tolerance due in part to reduced expression of hepatic glucokinase, and hyperammonemia from reduced expression of hepatic carbamoyl phosphate synthase-I. These mice also had reduced serum cholesterol and steatotic livers that was exacerbated with aging. This phenotype could be explained by increased expression of hepatic lipoprotein lipase and reduced expression of microsomal triglyceride transfer protein, apolipoproteins B100, and A-IV. These data demonstrate that hepatic C/EBPalpha is critical for ammonia detoxification and glucose and lipid homeostasis in adult mice.
Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yusuke
Y
Inoue
Junko
J
Inoue
Gilles
G
Lambert
Sun Hee
SH
Yim
Frank J
FJ
Gonzalez
D000375:Aging; D000641:Ammonia / Q000097:blood / Q000378:metabolism*; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis*; D002784:Cholesterol / Q000378:metabolism; D002853:Chromatography, Liquid; D015536:Down-Regulation; D005838:Genotype; D005941:Glucokinase / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000096:biosynthesis; D007003:Hypoglycemia / Q000378:metabolism; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010641:Phenotype; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution; D014508:Urea / Q000378:metabolism
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D022763:CCAAT-Enhancer-Binding Protein-alpha; D000641:Ammonia; D014508:Urea; D006003:Glycogen; D002784:Cholesterol; D006006:Glycogen Synthase; D005941:Glucokinase; D008071:Lipoprotein Lipase; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose