Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 3
Liver steatosis alters the expression of nuclear receptors and genes involved in bile acid
metabolism
Patricia Aspichueta, Oscar Briz, Lourdes Palacios, Ainara Cano, Xabier Buqué, Jose J.
Marín, Begoña Ochoa
Department of Physiology, University of the Basque Country, Faculty of Medicine and
Dentistry, Leioa, Spain. Email: patricia.aspichueta@ehu.es
Accumulation of fat within hepatocytes is a simple steatosis and a sign of lipotoxicity that is
frequently associated with changes in bile acid metabolism and cholestasis. The aim of this
work was to analyze whether transport proteins and cytochromes involved in bile acid
synthesis and secretion as well as some regulatory nuclear receptors are altered in obesityrelated
steatosis at the mRNA expression level. For this purpose, we i) isolated hepatocytes
from obese Zucker rats, an established model for non-alcoholic fatty liver disease, of 6, 9 and
12 weeks of age -hence, in three stages of steatosis- and from their lean littermates, ii)
extracted the RNA from hepatocytes, and iii) determined specific transcript levels by realtime
PCR. Our results showed that the mRNA levels of Cyp7a1 were 60% and 40% decreased
in the 6- and 12-week old steatotic animal while those of Cyp27a1 were similar to lean rat
hepatocytes. There was a dramatic decrease (of ,98%) in ABCG8 mRNA levels in the three
steatotic groups, accompanied by an important, though less marked decrease in ABCG5
expression. No changes were found in the mRNA levels of the transporters Bsep, mdr2, mrp2
and Ntcp. Discordant changes were observed between several major nuclear receptors and
their regulated target genes. Particularly, the transcription factors studied involved in Cyp7a1
expression regulation do not seem to be responsible for the changes observed in this study.
The mRNA levels of farnesoid X receptor (FXR) were modified in none of the obesity-related
steatotic groups, of the small heterodimer partner (SHP) were doubled only in 9 week-old
obese rat hepatocytes and of the alpha-fetoprotein transcription factor (FTF) were increased in
the three stages of liver steatosis. In conclusion, our results suggest that repression of Cyp7a1
in obesity-related steatosis may be linked to down-regulation of ABCG5, ABCG8 and LXR,
rather than to the mediation of mechanisms controlled by the FXR/SHP/FTF cascade.
Supported by Grant G03/015 from the Ministerio de Sanidad y Consumo
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