title: Exogenous FABP4 induces endoplasmic reticulum stress in HepG2 liver cells.
abstract: Fatty acid binding protein 4 (FABP4) is an intracellular fatty acid (FA) carrier protein that is, in part, secreted into circulation. Circulating FABP4 levels are increased in obesity, diabetes and other insulin resistance (IR) diseases. FAs contribute to IR by promoting endoplasmic reticulum stress (ER stress) and altering the insulin signaling pathway. The effect of FABP4 on ER stress in the liver is not known. The aim of this study was to investigate whether exogenous FABP4 (eFABP4) is involved in the lipid-induced ER stress in the liver.
  
  
  
  HepG2 cells were cultured with eFABP4 (40 ng/ml) with or without linoleic acid (LA, 200 μM) for 18 h. The expression of ER stress-related markers was determined by Western blotting (ATF6, EIF2α, IRE1 and ubiquitin) and real-time PCR (ATF6, CHOP, EIF2α and IRE1). Apoptosis was studied by flow cytometry using Annexin V-FITC and propidium iodide staining.
  
  
  
  eFABP4 increased the ER stress markers ATF6 and IRE1 in HepG2 cells. This effect led to insulin resistance mediated by changes in AKT and JNK phosphorylation. Furthermore, eFABP4 significantly induced both apoptosis, as assessed by flow cytometry, and CHOP expression, without affecting necrosis and ubiquitination. The presence of LA increased the ER stress response induced by eFABP4.
  
  
  
  eFABP4, per se, induces ER stress and potentiates the effect of LA in HepG2 cells, suggesting that FABP4 could be a link between obesity-associated metabolic abnormalities and hepatic IR mechanisms.
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Bosquet
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guaita-Esteruelas
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Saavedra
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Heras
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Girona
authors.affiliation: Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Universitat Rovira i Virgili, Reus, Spain. Electronic address: luis.masana@urv.cat.
authors.forename: Lluís
authors.initials: L
authors.lastname: Masana
mesh_terms: D017209:Apoptosis; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D008055:Lipids; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases
keywords: Apoptosis; Fatty acid; Fatty acid/binding protein; Fatty acid/transport; Hepatocytes; Linoleate; Signal transduction