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Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity

Maria Kolak¹, Jukka Westerbacka², Vidya R. Velagapudi³, Dick Wågsäter¹, Laxman Yetukuri³, Janne Makkonen^2,4, Aila Rissanen⁵, Anna-Maija Häkkinen⁶, Monica Lindell¹, Robert Bergholm^2,4, Anders Hamsten¹, Per Eriksson¹, Rachel M. Fisher¹, Matej Orei³, and Hannele Yki-Järvinen^1,2

¹ Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden
² Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland
³ VTT Technical Research Centre of Finland, Espoo, Finland
⁴ Minerva Medical Research Institute, Helsinki, Finland
⁵ Obesity Research Unit, University of Helsinki, Helsinki, Finland
⁶ Department of Oncology, University of Helsinki, Helsinki, Finland

Address correspondence and reprint requests to Hannele Yki-Järvinen, MD, P.O. Box 700, Room C426B, Biomedicum, Haartmaninkatu 8, 00029 HUS, Helsinki, Finland. E-mail: ykijarvi{at}cc.helsinki.fi

Abbreviations: LFAT, liver fat; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; PAI, plasminogen activator inhibitor; PPAR, proliferator–activated receptor; TNF-, tumor necrosis factor-

OBJECTIVE— We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.

RESEARCH DESIGN AND METHODS— A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 ± 0.3 vs. 14.4 ± 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.

RESULTS— Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator–activated receptor- and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.

CONCLUSIONS— Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.

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