title: Hyperketonemia induces upregulation of LFA-1 in monocytes, which is mediated by ROS and P38 MAPK activation.
abstract: Type 1 diabetic patients have hyperketonemia, elevated levels of pro-inflammatory and oxidative stress markers, and a higher incidence of vascular disease. This study examines the hypothesis that hyperketonemia increases reactive oxygen species (ROS) and is in part responsible for increased expression of adhesion molecules in monocytes. THP-1 monocytes were treated with acetoacetate (AA) or β-hydroxybutyrate (BHB) (0-10 mmol/L) for 24 h. Results show that AA, but not BHB, increases ROS production in monocytes. Pretreatment of monocytes with N-acetylcysteine (NAC) inhibited AA-induced ROS production. AA treatment induced upregulation of LFA-1 and pretreatment of monocytes with NAC or an inhibitor to p38 MAPK inhibited this upregulation in monocytes. This suggests that physiological concentrations of AA can contribute to increased ROS and activation of p38 MAPK, which may be responsible for AA-induced upregulation of LFA-1 in monocytes. Thus, hyperketonemia contributes to the risk for cardiovascular disease in type 1 diabetes.
authors.affiliation: Department of Pediatrics and Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Rains
authors.forename: Preeti
authors.initials: P
authors.lastname: Kanikarla-Marie
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Jain
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000090:Acetoacetates / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007662:Ketosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000090:Acetoacetates; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D017382:Reactive Oxygen Species; C016635:acetoacetic acid; D048051:p38 Mitogen-Activated Protein Kinases; D020155:3-Hydroxybutyric Acid; D000111:Acetylcysteine