Intestine‐Specific Overactivation of SREBP2 in Mice Increases Plasma Cholesterol

S terol R esponse E lement B inding P rotein 2 (SREBP2) transcription factor is a master regulator of cholesterol homeostasis. Treatment with statins, inhibitors of cholesterol synthesis, activates intestinal SREBP2 that may hinder their cholesterol‐lowering 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 (Chol) and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly increased in ISR2 vs wild type mice (wt) (Chol: 20.2±1.5 vs 15.9±1.2; TG: 82.3±14.9 vs 30.4±4.9; Chol: 40.5±3.1 vs 22.7±0.9; TG: 83.1±3.1 vs. 50.8±3.6, respectively). Serum Chol was significantly increased in VLDL and LDL fractions in ISR2 vs wt mice (15.92±2.3 vs 5.8±2 and 50.36±5 vs 16.05±0.5 mg/dl, respectively). 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. (Supported by VA and NIDDK).