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Diabetes Publish Ahead of Print published online ahead of print August 17, 2007
DOI: 10.2337/db07-0156
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Original Research

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 Westerbacka, MD1, Maria Kolak, PhD2, Tuula Kiviluoto, MD3, Perttu Arkkila, MD4, Jukka Sirén, MD3, Anders Hamsten, MD2, Rachel M. Fisher, PhD2, and Hannele Yki-Järvinen, MD1,,5

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

Correspondence: jukka.westerbacka{at}helsinki.fi

Objective: 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 non-alcoholic 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: PPARG2 (2.8-fold), the monocyte-attracting chemokine CCL2 (MCP-1, 1.8-fold) and four genes associated with fatty acid metabolism: ACSL4 (2.8-fold), FABP4 (3.9-fold), FABP5 (2.5-fold) and LPL (3.6-fold). PGC1 was significantly lower in subjects with NAFL than in those without. Genes significantly associated with obesity included 9 genes [(PAI1, PPARG, PPARD, MCP-1, CCL3 (MIP-1{alpha}), PPARG2, CPT1A, FABP4, 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.

Conclusion: 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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