Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis

Published:March 15, 2012DOI:

      Background & Aims

      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.


      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.


      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.


      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.


      NASH (non-alcoholic steatohepatitis), LPS (lipopolysaccharide), KC (Kupffer cell), NAFLD (non-alcoholic fatty liver disease), TNFα (tumor necrosis factor-α), IFNγ (interferon-γ), IL (interkeukin), ND (normal diet), HFD (high fat diet), TG (triacylglycerol), NPC (non-parenchymateous cells), TOFA (5-(tetradecyloxy)-2-furoic acid), TLDA (TaqMan low density array), OGTT (oral glucose tolerance test), HOMA (homeostasis model assessment of insulin-resistance), ALT (alanine aminotransferase), CCL (C-C motif chemokine ligand), ATM (adipose tissue macrophages), FA (fatty acid), FAS (fatty acid synthase), ACC1 (acetyl-CoA carboxylase 1), ChREBP (carbohydrate-responsive element binding protein), PPAR (peroxisome proliferator-activated receptor), FABP (fatty acid-binding protein), FATP5 (fatty acid transport protein 5), DGAT (diacylglycerol acyltransferase), SCD1 (stearoyl-CoA desaturase 1), CPT1A (carnitine parmitoyltransferase 1A), HMG-CoA (β-hydroxy-β-methylglutaryl coenzyme A), ACAT1 (acyl-CoA cholesterol acyltransferase 1), CE (cholesterol esters), ABCA6 (ATP binding cassette transporter A6), MARCO (macrophage receptor with collagenous structure), LDL (low-density lipoprotein), TLR (toll like receptors), MTP (microsomal triglyceride transfer protein), VLDL (very low-density lipoprotein), LXRα (liver X receptors alpha), MSR1 (SR-AI) (macrophage scavenger receptor), FC (free cholesterol), DAG (diacylglycerol), CXCL10 (C-X-C motif chemokine 10), SREBP1c (sterol regulatory element binding proteins isoform 1c), SR-PSOX (scavenger receptor binding phosphatidylserine and oxidized lipoprotein)


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