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Diabetes. 2007 Nov;56(11):2759-65. Epub 2007 Aug 17.

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.

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1
Department of Medicine, Division of Diabetes, University of Helsinki, P.O. Box 700, Room C418b, FIN-00029 HUCH, Helsinki, Finland. jukka.westerbacka@helsinki.fi

Abstract

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]). PPARgamma 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, PPARgamma, PPARdelta, 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.

PMID:
17704301
DOI:
10.2337/db07-0156
[Indexed for MEDLINE]
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