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HNF4alpha contributes to glucose formation in aged rat hepatocytes.

Authors: Park, EY  Lee, CH  Lee, EK  Kim, JH  Cova, A  Lee, SK  Cho, SC  Kwak, CS  Song, KY  Park, SC  Jun, HS  Kim, KT 
Citation: Park EY, etal., Exp Gerontol. 2013 Dec;48(12):1518-25. doi: 10.1016/j.exger.2013.10.011. Epub 2013 Oct 29.
Pubmed: (View Article at PubMed) PMID:24177414
DOI: Full-text: DOI:10.1016/j.exger.2013.10.011

Aging-dependent physiological conditions are attributed to parenchymal structural changes to cellular functions in aged organisms. Compared to the young animals, the primary hepatocytes from old rats showed a higher glucose output and a higher expression of the key gluconeogenesis-regulating enzyme, phosphoenol pyruvate carboxykinase (PEPCK). The primary hepatocytes from old rats showed a higher glucose output and a higher expression of the key gluconeogenesis-regulating enzyme, phosphoenol pyruvate carboxykinase (PEPCK), compared with those from the young animals. The in situ hybridization study showed increased PEPCK mRNA expression in the aged liver tissues. The livers from old rats showed loosened hexagonal hepatic lobular structures, increased collagen accumulation, and high expression of the hypoxia marker hypoxia-inducible factor 1alpha (HIF1alpha). Hypoxia increased the PEPCK mRNA and protein expression levels in accordance with the HIF1alpha expression. PEPCK promoter luciferase reporter assay showed that hypoxia increased PEPCK through transcriptional activation. Furthermore, the hepatocyte nuclear factor alpha (HNF4alpha) protein, but not the HNF4alpha mRNA level, increased in parallel with the PEPCK mRNA expression under hypoxic conditions. Glucose production increased under hypoxic conditions, but this increment diminished by HNF4alpha siRNA in young hepatocytes. Moreover, increased glucose production from old rat hepatocytes was reversed by the down-regulation of HNF4alpha through a specific siRNA. This study suggests that the mild hypoxic conditions in response to aging-dependent hepatic structural changes may contribute to the induction of the gluconeogenic enzyme PEPCK through HNF4alpha protein stabilization.

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CRRD Object Information
CRRD ID: 10445837
Created: 2015-12-04
Species: All species
Last Modified: 2015-12-04
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.