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 1 ,
Maria Kolak 2 ,
Tuula Kiviluoto 3 ,
Perttu Arkkila 4 ,
Jukka Sirén 3 ,
Anders Hamsten 2 ,
Rachel M. Fisher 2 and
Hannele Yki-Järvinen 1 , 5
1 Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
2 Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Stockholm, Sweden
3 Department of Surgery, University of Helsinki, Helsinki, Finland
4 Department of Medicine, Division of Gastroenterology, University of Helsinki, Helsinki, Finland
5 Minerva Foundation Institute for Medical Research, Helsinki, Finland
Address correspondence and reprint requests to Jukka Westerbacka, MD, PhD, Department of Medicine, Division of Diabetes, University
of Helsinki, P.O. Box 700, Room C418b, FIN-00029 HUCH, Helsinki, Finland. E-mail: jukka.westerbacka{at}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)γ2 (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]). PPARγ 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, PPARγ, PPARδ, MCP-1, CCL3 (macrophage inflammatory protein [MIP]-1α), PPARγ2, 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-1α, 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.
ADIPOR, adiponectin receptor
CCR2, C-C motif chemokine receptor-2
FATP, fatty acid transport protein
FABP, fatty acid binding protein
FFA, free fatty acid
LPL, lipoprotein lipase
MCP, monocyte chemoattractant protein
MIP, macrophage inflammatory protein
NAFL, nonalcoholic fatty liver
NAFLD, NAFL disease
NASH, nonalcoholic steatohepatitis
PAI-1, plasminogen activator inhibitor 1
PGC1, PPARγ coactivator 1
PPAR, peroxisome proliferator–activated receptor
RPLP0, ribosomal protein, large P0
TBP, TATA-binding protein
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 17 August 2007. DOI: 10.2337/db07-0156.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received March 18, 2007.
Accepted August 10, 2007.
DIABETES...

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

10.2337/db07-0156