title: Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis.
abstract: OBJECTIVE
  Non-alcoholic steatohepatitis (NASH) is characterized by steatosis associated with liver inflammation. Steatosis causes recruitment of lymphocytes into the liver and this is worsened by lipopolysaccharides (LPS). As macrophages may be involved in the lymphocyte homing, we studied the role of lipids in determining the phenotype of Kupffer cells (KCs) at the stage of steatosis.
  
  
  METHODS
  Steatosis was induced in mice by a high fat diet. The turnover and the recruitment of KCs were analyzed in vivo by flow cytometry. KCs phenotype was assessed by optical and electron microscopy, cell culture and lymphocyte recruitment by in vitro chemotaxis. Lipidomic analysis was carried out by mass-spectrometry and gene expression analysis by TaqMan low density array.
  
  
  RESULTS
  Although the number of KCs was not modified in steatotic livers compared to normal livers, their phenotypes were different. Electron microscopy demonstrated that the KCs from fatty livers were enlarged and loaded with lipid droplets. Lipid synthesis and trafficking were dysregulated in fat-laden KCs and toxic lipids accumulated. Fat-laden KCs recruited more CD4+ T and B lymphocytes in response to LPS stimulation than did control KCs and produced high levels of pro-inflammatory cytokines/chemokines, which could be reversed by inhibition of lipogenesis.
  
  
  CONCLUSIONS
  Lipid accumulation in fat-laden KCs is due to a dysregulation of lipid metabolism and trafficking. Fat-laden KCs are "primed" to recruit lymphocytes and exhibit a pro-inflammatory phenotype, which is reversible with inhibition of lipogenesis.
authors.affiliation: INSERM U996, Clamart F-92140, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Leroux
authors.forename: Gladys
authors.initials: G
authors.lastname: Ferrere
authors.forename: Vanessa
authors.initials: V
authors.lastname: Godie
authors.forename: Frédéric
authors.initials: F
authors.lastname: Cailleux
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Renoud
authors.forename: Françoise
authors.initials: F
authors.lastname: Gaudin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Naveau
authors.forename: Sophie
authors.initials: S
authors.lastname: Prévot
authors.forename: Samira
authors.initials: S
authors.lastname: Makhzami
authors.forename: Gabriel
authors.initials: G
authors.lastname: Perlemuter
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cassard-Doulcier
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D004041:Dietary Fats / Q000378:metabolism / Q000633:toxicity; D064429:Fatty Acid Synthases / Q000235:genetics; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005234:Fatty Liver / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000502:physiology; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D009687:Nuclear Proteins / Q000235:genetics; D009765:Obesity / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics; D010641:Phenotype; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004041:Dietary Fats; C493405:Fabp2 protein, mouse; D050556:Fatty Acid-Binding Proteins; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047495:PPAR gamma; D014157:Transcription Factors; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases