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

Abstract

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-1α), 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-1α, 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.