title: HNF4α contributes to glucose formation in aged rat hepatocytes.
abstract: 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 1α (HIF1α). Hypoxia increased the PEPCK mRNA and protein expression levels in accordance with the HIF1α expression. PEPCK promoter luciferase reporter assay showed that hypoxia increased PEPCK through transcriptional activation. Furthermore, the hepatocyte nuclear factor α (HNF4α) protein, but not the HNF4α mRNA level, increased in parallel with the PEPCK mRNA expression under hypoxic conditions. Glucose production increased under hypoxic conditions, but this increment diminished by HNF4α siRNA in young hepatocytes. Moreover, increased glucose production from old rat hepatocytes was reversed by the down-regulation of HNF4α 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 HNF4α protein stabilization.
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-ku, Incheon 406-840, South Korea; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-ku, Incheon 406-840, South Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Lee
authors.forename: Eun Kyu
authors.initials: EK
authors.lastname: Lee
authors.forename: Jae Hyeong
authors.initials: JH
authors.lastname: Kim
authors.forename: Anthony
authors.initials: A
authors.lastname: Cova
authors.forename: Suk Keun
authors.initials: SK
authors.lastname: Lee
authors.forename: Sung Chun
authors.initials: SC
authors.lastname: Cho
authors.forename: Chung Shil
authors.initials: CS
authors.lastname: Kwak
authors.forename: Kye Yong
authors.initials: KY
authors.lastname: Song
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Park
authors.forename: Hee Sook
authors.initials: HS
authors.lastname: Jun
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051557:Hepatocyte Nuclear Factor 4; C497444:Hif1a protein, rat; C496594:Hnf4a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: Aging; Gluconeogenesis; Glucose; HNF4α; Hypoxia; PEPCK