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Int J Clin Exp Pathol 2010;3(7):675-680

Original Article
Hepatic steatosis causes induction of the chemokine RANTES in the absence of
significant hepatic inflammation

Georgi Kirovski, Erwin Gäbele, Christoph Dorn, Lukas Moleda, Christoph Niessen, Thomas S. Weiss, Hella Wobser, Doris Schacherer, Christa
Buechler, Hermann E. Wasmuth, Claus Hellerbrand

Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany; Center for Liver Cell Research, Department of
Surgery, University Hospital, Regensburg, Regensburg, Germany; Department of Medicine III, University Hospital Aachen, Aachen, Germany.

Received July 16, 2010; accepted July 31, 2010; available online August 2, 2010

Abstract: Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to cirrhosis. Hepatocellular lipid
accumulation is a hallmark of both nonalcoholic steatosis and steatohepatitis (NASH). The latter develops upon pro-inflammatory cell
infiltration and is widely considered as the first relevant pathophysiological step in NAFLD-progression. The chemokine CCL5/RANTES plays
an important role in the progression of hepatic inflammation and fibrosis. We here aimed to investigate its expression in NAFLD. Incubation of
primary human hepatocytes with palmitic acid induced a dose-dependent lipid accumulation, and corresponding dose-dependent RANTES
induction in vitro. Furthermore, we observed significantly elevated hepatic RANTES expression in a dietary model of NAFLD, in which mice were
fed a high-fat diet for 12 weeks. This diet induced significant hepatic steatosis but only minimal inflammation. In contrast to the liver, RANTES
expression was not induced in visceral adipose tissue of the group fed with high-fat diet. Finally, RANTES serum levels were elevated in
patients with ultrasound-diagnosed NAFLD. In conclusion, our data indicate hepatocytes as cellular source of elevated hepatic as well as
circulating RANTES levels in response to hepatic steatosis. Noteworthy, upregulation of RANTES in response to lipid accumulation occurs in
the absence of relevant inflammation, which further indicates that hepatic steatosis per se has pathophysiological relevance and should not be
considered as benign.(IJCEP1007006).

Keywords: Hepatic steatosis, liver cirrhosis, nonalcoholic steatosis, steatohepatitis, chemokine CCL5, RANTES, inflammation, Nonalcoholic
fatty liver disease (NAFLD)

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Address all correspondence to:
Claus Hellerbrand, M.D.
University of Regensburg
Department of Internal Medicine I
D-93042 Regensburg
Tel: +49-941-944-7155
Fax:    +49-941-944-7154