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:

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.

• Authors: Jukka Westerbacka, Maria Kolak, Tuula Kiviluoto, Perttu Arkkila, Jukka Sirén, Anders Hamsten, Rachel M Fisher, Hannele Yki-Järvinen
• Journal: Diabetes (Diabetes) Vol. 56 Issue 11 Pg. 2759-65 (Nov 2007) ISSN: 1939-327X [Electronic] United States
• PMID: 17704301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL2 protein, human
• Chemokine CCL2
• Fatty Acids
• PPAR gamma
• RNA, Messenger
• Lipoprotein Lipase

Topics

• Chemokine CCL2 (genetics)
• Fatty Acids (metabolism)
• Fatty Liver (enzymology, genetics)
• Gene Expression Regulation
• Gene Expression Regulation, Enzymologic
• Humans
• Insulin Resistance (physiology)
• Lipolysis (genetics)
• Lipoprotein Lipase (genetics)
• Macrophages (physiology)
• Monocytes (physiology)
• PPAR gamma (genetics)
• Polymerase Chain Reaction
• RNA, Messenger (genetics)
• Reference Values