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Am J Physiol Gastrointest Liver Physiol (April 3, 2008). doi:10.1152/ajpgi.00074.2008
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Submitted on February 14, 2008
Accepted on April 1, 2008

GENE EXPRESSION IN HUMAN NAFLD

Dario Greco1, Anna Kotronen2*, Jukka Westerbacka2, Oscar Puig1, Perttu Arkkila3, Tuula Kiviluoto4, Saara Laitinen5, Maria Kolak6, Rachel M Fisher7, Anders Hamsten6, Petri Auvinen1, and Hannele Yki-Jarvinen8

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

* To whom correspondence should be addressed. E-mail: anna.kotronen{at}helsinki.fi.

Background: Despite the high prevalence of non-alcoholic fatty liver disease (NAFLD), little is known of its pathogenesis based on study of human liver samples. Methods: By the use of Affymetrix GeneChips (17601 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 using sequence-based re-annotation of Affymetrix probes and a robust model-based normalization method. Results: 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. Conclusions: The data show that multiple changes in gene expression characterize simple steatosis.






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