Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling

Journal Article · Fri Feb 15 04:00:00 EST 2013 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2012.11.011· OSTI ID:22278213

Mathew, Jasmin; Loranger, Anne; Gilbert, Stéphane ^[1]; Faure, Robert ^[2]; Marceau, Normand ^[1]

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1. Centre de recherche en cancérologie de l'Université Laval and Centre de recherche du CHUQ (L'Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada)
2. Département de Pédiatrie, Université Laval and Centre de recherche du CHUQ (Centre Mère-Enfant), Québec, Qc, Canada G1V 4G2 (Canada)

As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling.

• OSTI ID: 22278213
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 4 Vol. 319; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATP
GLUCOSE
GLYCOGEN
GLYCOLYSIS
HEPATOMAS
HEXOKINASE
INSULIN
KERATIN
LIVER CELLS
MITOCHONDRIA