title: Novel role of TLR4 in NAFLD development: Modulation of metabolic enzymes expression.
abstract: The rise in the prevalence of obesity and metabolic syndrome turned NAFLD as the most common cause of chronic liver diseases worldwide. Although the role of toll like receptors, especially TLR4, as activators of inflammatory pathways in liver diseases is well established, our goal was to investigate if TLR4 activation could modulate metabolic lipid pathways and alter the onset of NAFLD. We used LDL receptor-deficient mice (LDLrKO) fed with an atherogenic diet as a model. The role of TLR4 activation was evaluated by crossing LDLrKO mice with the TLR4 knockout mice. Animals were fed for 12weeks with high-fat high-cholesterol diet (HFD) containing 18% saturated fat and 1.25% cholesterol. TLR4/LDLr KO mice presented lower triacylglyceride (TAG) plasma levels when compared to LDLrKO, despite the type of diet ingested. HFD induced TAG and cholesterol accumulation in the liver of all mice genotypes studied, but TLR4/LDLr KO presented lower TAG accumulation than LDLrKO mice. Gene expression of TAG synthesis enzymes (ApoB100, MTTP, GPAT1 and GPAT4) was not differentially altered in TLR4/LDLr KO and LDLrKO mice. On the other hand, TLR4 deficiency enhanced the expression of several enzymes involved in the oxidation of fatty acids, as follows: ACOX, CPT-1, MTPa, MTBb, PBE and 3-ketoacyl-CoA thiolase. Acyl-carnitine plasma profile showed an increase in C0 and C2 concentration in TLR4/LDLr KO group, corroborating the hypothesis of increased fat oxidation. Our results indicate that TLR4 may have an important role in the onset of steatosis, once its depletion enhances fatty acid oxidation in the liver of mice, preventing triglyceride accumulation.
authors.affiliation: Emergency Medicine Department, Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Darkiane Fernandes
authors.initials: DF
authors.lastname: Ferreira
authors.affiliation: Biochemistry Unit, ZIEL - Research Center for Nutrition and Food Sciences, Technische Universität München, Freising, Germany.
authors.forename: Jarlei
authors.initials: J
authors.lastname: Fiamoncini
authors.affiliation: Emergency Medicine Department, Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Iryna Hirata
authors.initials: IH
authors.lastname: Prist
authors.affiliation: Emergency Medicine Department, Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Suely Kubo
authors.initials: SK
authors.lastname: Ariga
authors.affiliation: Emergency Medicine Department, Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Heraldo Possolo
authors.initials: HP
authors.lastname: de Souza
authors.affiliation: Emergency Medicine Department, Medical School, University of São Paulo, São Paulo, Brazil. Electronic address: thais@emercli.fm.usp.br.
authors.forename: Thais Martins
authors.initials: TM
authors.lastname: de Lima
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000009:adverse effects / Q000494:pharmacology; D004036:Diet, Atherogenic / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D005227:Fatty Acids / Q000009:adverse effects / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D002784:Cholesterol
keywords: Acyl-carnitine profile; Fatty acid oxidation; High-fat diet; LDL receptor knockout; Non-alcoholic fatty liver disease; Toll like receptor 4