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Published online August 17, 2007
Diabetes 56:2759-2765, 2007
DOI: 10.2337/db07-0156
© 2007 by the American Diabetes Association
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Genes Involved in Fatty Acid Partitioning and Binding, Lipolysis, Monocyte/Macrophage Recruitment, and Inflammation Are Overexpressed in the Human Fatty Liver of Insulin-Resistant Subjects

Jukka Westerbacka1, Maria Kolak2, Tuula Kiviluoto3, Perttu Arkkila4, Jukka Sirén3, Anders Hamsten2, Rachel M. Fisher2, and Hannele Yki-Järvinen1,5

1 Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
2 Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Stockholm, Sweden
3 Department of Surgery, University of Helsinki, Helsinki, Finland
4 Department of Medicine, Division of Gastroenterology, University of Helsinki, Helsinki, Finland
5 Minerva Foundation Institute for Medical Research, Helsinki, Finland

Address correspondence and reprint requests to Jukka Westerbacka, MD, PhD, Department of Medicine, Division of Diabetes, University of Helsinki, P.O. Box 700, Room C418b, FIN-00029 HUCH, Helsinki, Finland. E-mail: jukka.westerbacka{at}helsinki.fi

Abbreviations: ADIPOR, adiponectin receptor; CCR2, C-C motif chemokine receptor-2; FATP, fatty acid transport protein; FABP, fatty acid binding protein; FFA, free fatty acid; LPL, lipoprotein lipase; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; NAFL, nonalcoholic fatty liver; NAFLD, NAFL disease; NASH, nonalcoholic steatohepatitis; PAI-1, plasminogen activator inhibitor 1; PGC1, PPAR{gamma} coactivator 1; PPAR, peroxisome proliferator–activated receptor; RPLP0, ribosomal protein, large P0; TBP, TATA-binding protein

OBJECTIVE—The objective of this study is to quantitate expression of genes possibly contributing to insulin resistance and fat deposition in the human liver.

RESEARCH DESIGN AND METHODS—A total of 24 subjects who had varying amounts of histologically determined fat in the liver ranging from normal (n = 8) to steatosis due to a nonalcoholic fatty liver (NAFL) (n = 16) were studied. The mRNA concentrations of 21 candidate genes associated with fatty acid metabolism, inflammation, and insulin sensitivity were quantitated in liver biopsies using real-time PCR. In addition, the subjects were characterized with respect to body composition and circulating markers of insulin sensitivity.

RESULTS—The following genes were significantly upregulated in NAFL: peroxisome proliferator–activated receptor (PPAR){gamma}2 (2.8-fold), the monocyte-attracting chemokine CCL2 (monocyte chemoattractant protein [MCP]-1, 1.8-fold), and four genes associated with fatty acid metabolism (acyl-CoA synthetase long-chain family member 4 [ACSL4] [2.8-fold], fatty acid binding protein [FABP]4 [3.9-fold], FABP5 [2.5-fold], and lipoprotein lipase [LPL] [3.6-fold]). PPAR{gamma} coactivator 1 (PGC1) was significantly lower in subjects with NAFL than in those without. Genes significantly associated with obesity included nine genes: plasminogen activator inhibitor 1, PPAR{gamma}, PPAR{delta}, MCP-1, CCL3 (macrophage inflammatory protein [MIP]-1{alpha}), PPAR{gamma}2, carnitine palmitoyltransferase (CPT1A), FABP4, and FABP5. The following parameters were associated with liver fat independent of obesity: serum adiponectin, insulin, C-peptide, and HDL cholesterol concentrations and the mRNA concentrations of MCP-1, MIP-1{alpha}, ACSL4, FABP4, FABP5, and LPL.

CONCLUSIONS—Genes involved in fatty acid partitioning and binding, lipolysis, and monocyte/macrophage recruitment and inflammation are overexpressed in the human fatty liver.


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Copyright © 2007 by the American Diabetes Association.