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Am J Physiol Gastrointest Liver Physiol 294: G1281-G1287, 2008. First published April 3, 2008; doi:10.1152/ajpgi.00074.2008
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LIVER AND BILIARY TRACT

Gene expression in human NAFLD

Dario Greco,1,* Anna Kotronen,2,3,* Jukka Westerbacka,2 Oscar Puig,1 Perttu Arkkila,4 Tuula Kiviluoto,5 Saara Laitinen,3 Maria Kolak,6 Rachel M. Fisher,6 Anders Hamsten,6 Petri Auvinen,1 and Hannele Yki-Järvinen2

1Institute of Biotechnology, University of Helsinki; 2Department of Medicine, Division of Diabetes, University of Helsinki; 3Minerva Medical Research Institute, Helsinki; 4Department of Medicine, Division of Gastroenterology, University of Helsinki; and 5Department of Surgery, University of Helsinki, Helsinki, Finland; and 6Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

Submitted 14 February 2008 ; accepted in final form 1 April 2008

Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), little is known of its pathogenesis based on study of human liver samples. By the use of Affymetrix GeneChips (17,601 genes), we investigated gene expression in the human liver of subjects with extreme steatosis due to NAFLD without histological signs of inflammation (liver fat 66.0 ± 6.8%) and in subjects with low liver fat content (6.4 ± 2.7%). The data were analyzed by using sequence-based reannotation of Affymetrix probes and a robust model-based normalization method. We identified genes involved in hepatic glucose and lipid metabolism, insulin signaling, inflammation, coagulation, and cell adhesion to be significantly associated with liver fat content. In addition, genes involved in ceramide signaling (MAP2K4) and metabolism (UGCG) were found to be positively associated with liver fat content. Genes involved in lipid metabolism (PLIN, ACADM), fatty acid transport (FABP4, CD36), amino acid catabolism (BCAT1), and inflammation (CCL2) were validated by real-time PCR and were found to be upregulated in subjects with high liver fat content. The data show that multiple changes in gene expression characterize simple steatosis.

liver fat; nonalcoholic fatty liver disease; lipid metabolism; inflammation; ceramides


Address for reprint requests and other correspondence: H. Yki-Järvinen, Dept. of Medicine, Division of Diabetes, Univ. of Helsinki, Finland; P. O. Box 700, Rm. C426B, FIN - 00029 HUCH, Helsinki, Finland






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