title: Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet-Fed Mice.
abstract: Subclinical circulating bacterial endotoxin LPS has been implicated as an important cofactor in the development and progression of nonalcoholic steatohepatitis, but the underlying mechanisms remain unclear. In this study, we demonstrated that 4-wk injection with superlow-dose LPS significantly promoted neutrophil infiltration and accelerated nonalcoholic steatohepatitis progression, including exacerbated macrovesicular steatosis, inflammation, and hepatocyte ballooning in high-fat diet-fed apolipoprotein E knockout mice. This effect could sustain for a month after stoppage of LPS injection. LPS also significantly increased numbers of apoptotic nuclei in hepatocytes and expressions of proapoptotic regulators. Moreover, LPS sustained the low-grade activation of p38 MAPK and inhibited the expression of the upstream MAPK phosphatase 7. By applying selective inhibitors, we demonstrated that the activation of p38 MAPKs is required for neutrophil migration induced by superlow-dose LPS in vitro. Together, these data suggest that superlow-dose LPS may sustain the low-grade activation of p38 MAPKs and neutrophil infiltration, leading to the exacerbation of steatohepatitis.
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.|Department of Nutrition, Henry Fok School of Food Science and Engineering, Shaoguan University, Shaoguan 512005, China.
authors.forename: Honghui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.|Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Na
authors.initials: N
authors.lastname: Diao
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.affiliation: Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Mingsong
authors.initials: M
authors.lastname: Li
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D004731:Endotoxins / Q000008:administration & dosage*; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D008954:Models, Biological; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D004731:Endotoxins; D008055:Lipids; D008070:Lipopolysaccharides; D048051:p38 Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C438002:Dusp16 protein, mouse
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