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Overactivation of intestinal SREBP2 in mice increases serum cholesterol

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journal contribution
posted on 03.06.2015, 00:00 by K. Ma, P. Malhotra, V. Soni, O. Hedroug, F. Annaba, A. Dudeja
Sterol Response Element Binding Protein 2 (SREBP2) transcription factor is a master regulator of cholesterol homeostasis. Treatment with statins, inhibitors of cholesterol synthesis, activates intestinal SREBP2, which may hinder their cholesterollowering effects. Overactivation of SREBP2 in mouse liver was shown to have no effect on plasma cholesterol. However, the influence of activating intestinal SREBP2 on plasma cholesterol is not known. We have generated a novel transgenic mouse model with intestine specific overexpression of active SREBP2 (ISR2) driven by villin promoter. ISR2 mice showed overexpression of active SREBP2 specifically in the intestine. Microarray analysis of jejunal RNA from ISR2 mice showed a significant increase in genes involved in fatty acid and cholesterol synthesis. Cholesterol and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly increased in ISR2 vs wild type mice. Serum Cholesterol was significantly increased in VLDL and LDL fractions whereas the level of serum triglycerides was decreased in ISR2 vs wild type mice. In conclusion, activation of intestinal SREBP2 alone seems to be sufficient to increase plasma cholesterol, highlighting the essential role of intestine in maintaining cholesterol homeostasis in the body.




These studies were supported by the Department of Veterans Affairs (WAA, PKD) and the following NIDDK grants: DK54016, DK81858, DK92441 (PKD), DK96258 (RKG), DK96245 (SS), and DK71596 (WAA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip


Publisher Statement

This is the copy of an article published in PLoS One. 2014. 9(1):e84221. DOI: 10.1371/journal.pone.0084221.


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