Selective insulin resistance in hepatocyte senescence

Aloysious Aravinthan; Benjamin Challis; Nicholas Shannon; Matthew Hoare; Judith Heaney; Graeme J M Alexander

doi:10.1016/j.yexcr.2014.09.025

Selective insulin resistance in hepatocyte senescence

Exp Cell Res. 2015 Feb 1;331(1):38-45. doi: 10.1016/j.yexcr.2014.09.025. Epub 2014 Sep 28.

Authors

Aloysious Aravinthan¹, Benjamin Challis², Nicholas Shannon³, Matthew Hoare⁴, Judith Heaney⁵, Graeme J M Alexander⁶

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK.
² Institute of Metabolic Sciences, University of Cambridge, Cambridge, UK.
³ Cancer Research UK Cambridge Institute, Cambridge, UK.
⁴ Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Institute, Cambridge, UK.
⁵ Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Foundation for Liver Research, Institute of Hepatology, London, UK.
⁶ Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: gja1000@doctors.org.uk.

PMID: 25263463
DOI: 10.1016/j.yexcr.2014.09.025

Abstract

Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence.

Keywords: Chronic liver disease; Hepatocyte senescence; Selective insulin resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers / metabolism*
Blotting, Western
Cellular Senescence / drug effects*
Forkhead Box Protein O1
Forkhead Transcription Factors / metabolism
Glucose Transporter Type 2 / metabolism
Glucose Transporter Type 4 / metabolism
Hep G2 Cells
Hepatocytes / drug effects
Hepatocytes / metabolism
Hepatocytes / pathology*
Humans
Hypoglycemic Agents / pharmacology
Insulin / pharmacology*
Insulin Resistance*
Liver Diseases / drug therapy
Liver Diseases / metabolism
Liver Diseases / pathology*
Oxidative Stress / drug effects
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism

Substances

Biomarkers
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
Glucose Transporter Type 2
Glucose Transporter Type 4
Hypoglycemic Agents
Insulin
SLC2A2 protein, human
SLC2A4 protein, human
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt