Modulation of Hepatic Transcriptome in the Poloxamer P-407 Hyperlipidemia Mouse Model
Drago Kuzman,1,* Klementina Fon Tacer,2 M. Černe,1 Tadeja Režen,2 Jure Ačimovič,2 Urška Čegovnik,3 Darko Kocjan,1 Uroš Urleb1 and Damjana Rozman2
1 Lek Pharmaceuticals d.d., Ljubljana, Slovenia
2 Centre for Functional Genomics and Bio-Chips,
Faculty of Medicine, University of Ljubljana, Slovenia
3 University Clinic for Pulmonary and Allergic
Diseases Golnik, Golnik, Slovenia
* Corresponding author: E-mail:
drago.kuzman@sandoz.com
Abstract
The poloxamer P-407 hyperlipidemia mouse is a genetically unaltered, nondiet-induced
model of atherosclerosis which is useful in studying effects of lipid lowering
drugs. While the model is relatively well described on the biochemical level,
the knowledge regarding the global gene expression was lacking so far. As
expected, the P-407 elevates plasma triglycerides and cholesterol. Using
microarray analysis and RT-PCR we show for the first time that poloxamer
triggers a concerted modulation of hepatic genes involved in multiple steps of
atherogenesis, such as lipid metabolism, initiation of atherogenesis, lesion
formation, and atheroma progression. 106 hepatic genes were upregulated and only
40 downregulated, suggesting that upregulation of atherogenic genes precedes the
atheroma formation. Modulated expression of circadian genes has also been
observed in this type of hyperlipidemia but further studies are needed to
elucidate whether this effects the rhythm of animals.
Keywords: Poloxamer, hyperlipidemia, atherogenesis, circadian