title: Hyperreactivity of Blood Leukocytes in Patients with NAFLD to Ex Vivo Lipopolysaccharide Treatment Is Modulated by Metformin and Phosphatidylcholine but Not by Alpha Ketoglutarate.
abstract: OBJECTIVE
  Toll-like receptor 4 and proinflammatory cytokines play a central role in the progression of nonalcoholic fatty liver disease. We investigated IL-1, IL-6 and TNFα production and toll-like receptor 4 in both--obese and lean patients with non-alcoholic fatty liver disease who met different sets of metabolic syndrome criteria and linked the results with the disease burden.
  
  
  METHODS
  95 subjects were divided into four groups depending on the following criteria: presence or absence of metabolic syndrome and/or non-alcoholic fatty liver disease, glucose tolerance (prediabetes or normoglycemia) and BMI value (obese or lean). We determined the levels of IL-1β, IL-6, TNFα, and monocyte toll-like receptor 4 expression in fresh blood as well as in blood cultures treated with lipopolysaccharide with or without metformin, alphaketoglutarate or phosphatidylcholine supplementation.
  
  
  RESULTS
  The blood leukocytes of patients with non-alcoholic fatty liver disease are hypersensitive to lipopolysaccharide treatment and produce elevated levels of pro-inflammatory cytokines in response to ex vivo treatment with lipopolysaccharide. Moreover, they overexpress toll-like receptor-4. Hyperreactivity was typical mainly for obese patients with non-alcoholic fatty liver disease together with metabolic syndrome and decreased with the severity of disease. Metformin was the most effective in attenuation of hyperreactivity in all groups of patients with non-alcoholic fatty liver disease, but in obese patients the effectiveness of metformin was weaker than in lean. The reduction of cytokine level by metformin was accompanied by the decrease in toll-like receptor-4 expression. phosphatidylcholine also attenuated hyperreactivity to lipopolysaccharide but mainly in obese patients. Alpha ketoglutarate did not modulate cytokines' level and toll-like receptor 4 expression in non-alcoholic fatty liver disease patients.
  
  
  CONCLUSIONS
  Metformin and phosphatidylcholine attenuated lipopolysaccharide induced toll-like receptor 4 overexpression and overproduction of pro-inflammatory cytokines; however, their efficacy depended on combined presence of non-alcoholic fatty liver disease, metabolic syndrome and obesity.
authors.affiliation: Chair of Internal Medicine and Department of Internal Nursing, Medical University of Lublin, Lublin, Poland.|Department and Clinic of Endocrinology, Medical University of Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zwolak
authors.affiliation: Department of Virology and Immunology, Maria Curie-Sklodowska University, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szuster-Ciesielska
authors.affiliation: Chair of Internal Medicine and Department of Internal Nursing, Medical University of Lublin, Lublin, Poland.|Department and Clinic of Gastroenterology, Medical University of Lublin, Lublin, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Daniluk
authors.affiliation: Department of Virology and Immunology, Maria Curie-Sklodowska University, Lublin, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Słabczyńska
authors.affiliation: Department of Virology and Immunology, Maria Curie-Sklodowska University, Lublin, Poland.
authors.forename: Martyna
authors.initials: M
authors.lastname: Kandefer-Szerszeń
mesh_terms: D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000378:metabolism; D009765:Obesity / Q000150:complications; D010713:Phosphatidylcholines / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D016207:Cytokines; D007656:Ketoglutaric Acids; D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D008687:Metformin