title: Selective insulin resistance in hepatocyte senescence.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Aloysious
authors.initials: A
authors.lastname: Aravinthan
authors.affiliation: Institute of Metabolic Sciences, University of Cambridge, Cambridge, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Challis
authors.affiliation: Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shannon
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Institute, Cambridge, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoare
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Foundation for Liver Research, Institute of Hepatology, London, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Heaney
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK. Electronic address: gja1000@doctors.org.uk.
authors.forename: Graeme J M
authors.initials: GJM
authors.lastname: Alexander
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D016922:Cellular Senescence / Q000187:drug effects*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D015415:Biomarkers; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495680:SLC2A2 protein, human; C495692:SLC2A4 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Chronic liver disease; Hepatocyte senescence; Selective insulin resistance