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

Exp Cell Res. 2013 Feb 15;319(4):474-86. doi: 10.1016/j.yexcr.2012.11.011. Epub 2012 Nov 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Glucose / metabolism*
  • Glucose Transport Proteins, Facilitative / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Hexokinase / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Keratin-18 / metabolism
  • Keratin-18 / physiology*
  • Keratin-8 / metabolism
  • Keratin-8 / physiology*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Glucose Transport Proteins, Facilitative
  • Insulin
  • Keratin-18
  • Keratin-8
  • Hexokinase
  • Glucose