title: Tlr4-mutant mice are resistant to acute alcohol-induced sterol-regulatory element binding protein activation and hepatic lipid accumulation.
abstract: Previous studies demonstrated that acute alcohol intoxication caused hepatic lipid accumulation. The present study showed that acute alcohol intoxication caused hepatic lipid accumulation in Tlr4-wild-type mice but not in Tlr4-mutant mice. Hepatic sterol-regulatory element binding protein (SREBP)-1, a transcription factor regulating fatty acid and triglyceride (TG) synthesis, was activated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Hepatic Fas, Acc, Scd-1 and Dgat-2, the key genes for fatty acid and TG synthesis, were up-regulated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Additional experiment showed that hepatic MyD88 was elevated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Hepatic NF-κB was activated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Moreover, hepatic GSH content was reduced and hepatic MDA level was elevated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Hepatic CYP2E1 was elevated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Hepatic p67phox and gp91phox, two NADPH oxidase subunits, were up-regulated in alcohol-treated Tlr4-wild-type mice but not in Tlr4-mutant mice. Alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin-trapping agent, protected against alcohol-induced hepatic SREBP-1 activation and hepatic lipid accumulation. In conclusion, Tlr4-mutant mice are resistant to acute alcohol-induced hepatic SREBP-1 activation and hepatic lipid accumulation.
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Liu
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei, 230032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei, 230032, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Liu
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei, 230032, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000435:Alcoholic Intoxication / Q000378:metabolism; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005227:Fatty Acids / Q000096:biosynthesis; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D003497:Cyclic N-Oxides; D005227:Fatty Acids; D007328:Insulin; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D021122:Protein Subunits; D051780:Sterol Regulatory Element Binding Protein 1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014280:Triglycerides; C029217:phenyl-N-tert-butylnitrone; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt