Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3α-deficient mice
| Autor: | David Q. Shih, Stephen A. Duncan, Markus Stoffel, Navas Ma, Kuwajima S |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Hepatocyte Nuclear Factor 3-alpha
medicine.medical_specialty Genotype medicine.medical_treatment Restriction Mapping Biology digestive system Alpha cell Feeding and Eating Disorders Mice Internal medicine medicine Animals Homeostasis Glucose homeostasis Pancreatic islet function Pancreas Triglycerides Mice Knockout Multidisciplinary Wasting Syndrome Insulin Glucagon secretion Nuclear Proteins Feeding Behavior Biological Sciences Proglucagon Hypoglycemia DNA-Binding Proteins Death Hepatocyte nuclear factors Glucose Endocrinology Animals Newborn Starvation embryonic structures Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 96:10152-10157 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Hepatocyte nuclear factors 3 (HNF-3) belong to an evolutionarily conserved family of transcription factors that are critical for diverse biological processes such as development, differentiation, and metabolism. To study the physiological role of HNF-3alpha, we generated mice that lack HNF-3alpha by homologous recombination in embryonic stem cells. Mice homozygous for a null mutation in the HNF-3alpha gene develop a complex phenotype that is characterized by abnormal feeding behavior, progressive starvation, persistent hypoglycemia, hypotriglyceridemia, wasting, and neonatal mortality between days 2 and 14. Hypoglycemia in HNF-3alpha-null mice leads to physiological counter-regulatory responses in glucocorticoid and growth hormone production and an inhibition of insulin secretion but fails to stimulate glucagon secretion. Glucagon-producing pancreatic alpha cells develop normally in HNF-3alpha-/- mice, but proglucagon mRNA levels are reduced 50%. Furthermore, the transcriptional levels of neuropeptide Y are also significantly reduced shortly after birth, implying a direct role of HNF-3alpha in the expression of these genes. In contrast, mRNA levels were increased in HNF-3 target genes phosphofructo-2-kinase/fructose-2,6-bisphophatase, insulin growth factor binding protein-1, and hexokinase I of HNF-3alpha-null mice. Mice lacking one or both HNF-3alpha alleles also show impaired insulin secretion and glucose intolerance after an intraperitoneal glucose challenge, indicating that pancreatic beta-cell function is also compromised. Our results indicate that HNF-3alpha plays a critical role in the regulation of glucose homeostasis and in pancreatic islet function. |
| Databáze: | OpenAIRE |
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