Overactivation of intestinal SREBP2 in mice increases serum cholesterol.
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 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 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.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Ke
K
Ma
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Pooja
P
Malhotra
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Vinay
V
Soni
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Omar
O
Hedroug
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Fadi
F
Annaba
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Amish
A
Dudeja
Department of Surgery, University of Chicago, Chicago, Illinois, United States of America.
Le
L
Shen
Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
Jerrold R
JR
Turner
Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
Ekaterina A
EA
Khramtsova
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Seema
S
Saksena
Research and Development, Jesse Brown VA Medical Center, Chicago, Illinois, United States of America ; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Pradeep K
PK
Dudeja
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Ravinder K
RK
Gill
Research and Development, Jesse Brown VA Medical Center, Chicago, Illinois, United States of America ; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Waddah A
WA
Alrefai
D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D002784:Cholesterol