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

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 11; pp. 2759 - 2765
• Main Authors: WESTERBACKA, Jukka, KOLAK, Maria, KIVILUOTO, Tuula, ARKKILA, Perttu, SIREN, Jukka, HAMSTEN, Anders, FISHER, Rachel M, YKI-JÄRVINEN, Hannele
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2007
• Subjects: Biological and medical sciences; Biopsy; Body fat; Chemokine CCL2 - genetics; Chemokines; Diabetes; Diabetes. Impaired glucose tolerance; Diabetics; Disease; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids - metabolism; Fatty Liver - enzymology; Fatty Liver - genetics; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Genetic aspects; Health aspects; Hepatitis; Histology; Humans; Inflammation; Insulin resistance; Insulin Resistance - physiology; Lipolysis; Lipolysis - genetics; Lipoprotein Lipase - genetics; Lipoproteins; Liver cirrhosis; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Macrophages; Macrophages - physiology; Medical sciences; Metabolism; Monocytes; Monocytes - physiology; Obesity; Other diseases. Semiology; Physiological aspects; Polymerase Chain Reaction; PPAR gamma - genetics; Proteins; Recruitment; Reference Values; Research design; RNA, Messenger - genetics; Sweden; Finland; Endocrinopathy; Human; Pancreatic hormone; Monocyte; Diabetes mellitus; Lipids; Hepatic disease; Inflammation; Fatty acids; Insulin; Lipolysis; Recruitment; Fatty liver; Gene; Digestive diseases; Macrophage
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db07-0156

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