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


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.
Westerbacka
Jukka
J
Department of Medicine, Division of Diabetes, University of Helsinki, P.O. Box 700, Room C418b, FIN-00029 HUCH, Helsinki, Finland. jukka.westerbacka@helsinki.fi
Kolak
Maria
M
Kiviluoto
Tuula
T
Arkkila
Perttu
P
Sirén
Jukka
J
Hamsten
Anders
A
Fisher
Rachel M
RM
Yki-Järvinen
Hannele
H
D018932:Chemokine CCL2 / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics*; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008066:Lipolysis / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D005227:Fatty Acids; D047495:PPAR gamma; D012333:RNA, Messenger; D008071:Lipoprotein Lipase