title: Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Mathew
authors.forename: Anne
authors.initials: A
authors.lastname: Loranger
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gilbert
authors.forename: Robert
authors.initials: R
authors.lastname: Faure
authors.forename: Normand
authors.initials: N
authors.lastname: Marceau
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D053538:Keratin-18 / Q000378:metabolism / Q000502:physiology*; D053533:Keratin-8 / Q000378:metabolism / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D007328:Insulin; D053538:Keratin-18; D053533:Keratin-8; D006593:Hexokinase; D005947:Glucose