title: Changes in gluconeogenesis and intracellular lipid accumulation characterize uremic human hepatocytes ex vivo.
abstract: It is well known that reduced glomerular filtration rate (GFR) leads to an increased risk of dyslipidemia, insulin resistance, and cardiovascular mortality. The liver is a central organ for metabolism, but its function in the uremic setting is still poorly characterized. We used human primary hepatocytes isolated from livers of nine donors with normal renal function to investigate perturbations in key metabolic pathways following exposure to uremic (n = 8) or healthy (n = 8) sera, and to serum-free control medium. Both uremic and healthy elicited consistent responses from hepatocytes from multiple donors and compared with serum-free control. However, at physiological insulin concentrations, uremic cells accumulated 56% more intracellular lipids. Also, when comparing uremic with healthy medium after culture, it contained more very-low-density lipoprotein-triglyceride and glucose. These changes were accompanied by decreased phosphorylation of AktS473 mRNA levels of key regulators of gluconeogenesis in uremic sera-treated hepatocytes such as phosphoenolpyruvate carboxykinase 1 and glucose 6-phosphate were elevated. We also found increased expression of 11β-hydroxysteroid dehydrogenase mRNA in uremic cells, along with high phosphorylation of downstream p53 and phospholipase C-γ1Y783 Thus our ex vivo data suggest that the uremic hepatocytes rapidly develop a glycogenic and lipogenic condition accompanied by perturbations in a large number of signaling networks.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden;
authors.forename: Meng
authors.identifier: 0000-0002-7826-8707
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden;
authors.forename: Ewa
authors.initials: E
authors.lastname: Ellis
authors.affiliation: Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden;
authors.forename: Helene
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden;
authors.forename: Greg
authors.initials: G
authors.lastname: Nowak
authors.affiliation: Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden;
authors.forename: Bengt
authors.initials: B
authors.lastname: Isaksson
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden;
authors.forename: Davide
authors.initials: D
authors.lastname: Gnocchi
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden;
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; and Department of Immunology, Karolinska University Hospital, Stockholm, Sweden jonas.axelsson@ki.se.
authors.forename: Jonas
authors.initials: J
authors.lastname: Axelsson
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005943:Gluconeogenesis; D019298:Glucose-6-Phosphate / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000378:metabolism; D014511:Uremia / Q000097:blood / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D014280:Triglycerides; D019298:Glucose-6-Phosphate; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: dyslipidemia; human primary hepatocytes; insulin signaling; kidney disease