title: Hepatic interleukin-6 production is maintained during endotoxin tolerance and facilitates lipid accumulation.
abstract: Gut-derived bacterial endotoxins, such as lipopolysaccharide (LPS), contribute to the pathogenesis of steatosis and steatohepatitis by activating Kupffer cells, the resident liver macrophages. Exposure of macrophages to low doses of LPS causes hyporesponsiveness upon subsequent endotoxin challenge, a phenomenon termed endotoxin or LPS tolerance. In the present study, we aimed to examine whether LPS-induced lipid accumulation is affected by endotoxin tolerance. LPS pretreatment reduced the expression of proinflammatory mediators upon subsequent high-dose LPS treatment in murine livers. Total lipid and lipid class analysis indicated that LPS-induced lipid accumulation was not affected by endotoxin tolerance, although it was dependent on the presence of Kupffer cells. Analysis of the expression of lipogenic genes revealed that sterol regulatory element binding transcription factor 1 (Srebf1) and its target ELOVL fatty acid elongase 6 (Elovl6) were upregulated upon LPS administration in livers from LPS-tolerant and non-tolerant mice, whereas the expression of peroxisome proliferator activated receptor-α (Ppara), a key inducer of lipid degradation, was decreased. Neither Interleukin (IL)-6 expression nor the activation of its downstream effector signal transducer and activator of transcription (STAT) 3 were suppressed in liver tissues of LPS-tolerized mice. In vitro experiments confirmed that recombinant or macrophage-derived IL-6 was a potent activator of the lipogenic factor STAT3 in hepatocytes. Accordingly, IL-6 treatment led to increased lipid levels in this cell type. In summary, our data show that endotoxin tolerance does not influence LPS-induced hepatic lipid accumulation and suggest that IL-6 drives hepatic lipid storage.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Dembek
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Laggai
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Kessler
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Czepukojc
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Simon
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany. Electronic address: pharm.bio.kiemer@mx.uni-saarland.de.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoppstädter
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D000081031:Fatty Acid Elongases; D056945:Hep G2 Cells; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D015850:Interleukin-6 / Q000378:metabolism*; D007728:Kupffer Cells / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000235:genetics; D012772:Shock, Septic / Q000276:immunology* / Q000517:prevention & control; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
chemical_list: C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D047493:PPAR alpha; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases
keywords: ASH (alcoholic steatohepatitis); Clodronate; Endotoxemia; HepG2; Leaky gut; Monocyte-derived macrophages; NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); TLR4 (Toll-like receptor 4)