Abstract
SREBP-2 activates transcription of all genes needed for cholesterol biosynthesis. To study SREBP-2 function in the intestine, we generated a mouse model (Vil-BP2/) in which Cre recombinase ablates SREBP-2 in intestinal epithelia. Intestines of Vil-BP2/ mice had reduced expression of genes required for sterol synthesis, in vivo sterol synthesis rates, and epithelial cholesterol contents. On a cholesterol-free diet, the mice displayed chronic enteropathy with histological abnormalities of both villi and crypts, growth restriction, and reduced survival that was prevented by supplementation of cholesterol in the diet. Likewise, SREBP-2-deficient enteroids required exogenous cholesterol for growth. Blockade of luminal cholesterol uptake into enterocytes with ezetimibe precipitated acutely lethal intestinal damage in Vil-BP2/ mice, highlighting the critical interplay in the small intestine of sterol absorption via NPC1L1 and sterol synthesis via SREBP-2 in sustaining the intestinal mucosa. These data show that the small intestine requires SREBP-2 to drive cholesterol synthesis that sustains the intestinal epithelia when uptake of cholesterol from the gut lumen is not available, and provide a unique example of cholesterol auxotrophy expressed in an intact, adult mammal.—Rong, S., J. G. McDonald, and L. J. Engelking. Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1988-1998 |
| Number of pages | 11 |
| Journal | Journal of Lipid Research |
| Volume | 58 |
| Issue number | 10 |
| DOIs | |
| State | Published - 2017 |
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Keywords
- Cholesterol/biosynthesis
- Fatty acid/synthesis
- Niemann-Pick C1-like 1
- Organoid
- Scap
- SREBP
ASJC Scopus subject areas
- Biochemistry
- Endocrinology
- Cell Biology
Cite this
Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine. / Rong, Shunxing; McDonald, Jeffrey G.; Engelking, Luke J.
In: Journal of Lipid Research, Vol. 58, No. 10, 2017, p. 1988-1998.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine
AU - Rong, Shunxing
AU - McDonald, Jeffrey G.
AU - Engelking, Luke J.
PY - 2017
Y1 - 2017
N2 - SREBP-2 activates transcription of all genes needed for cholesterol biosynthesis. To study SREBP-2 function in the intestine, we generated a mouse model (Vil-BP2/) in which Cre recombinase ablates SREBP-2 in intestinal epithelia. Intestines of Vil-BP2/ mice had reduced expression of genes required for sterol synthesis, in vivo sterol synthesis rates, and epithelial cholesterol contents. On a cholesterol-free diet, the mice displayed chronic enteropathy with histological abnormalities of both villi and crypts, growth restriction, and reduced survival that was prevented by supplementation of cholesterol in the diet. Likewise, SREBP-2-deficient enteroids required exogenous cholesterol for growth. Blockade of luminal cholesterol uptake into enterocytes with ezetimibe precipitated acutely lethal intestinal damage in Vil-BP2/ mice, highlighting the critical interplay in the small intestine of sterol absorption via NPC1L1 and sterol synthesis via SREBP-2 in sustaining the intestinal mucosa. These data show that the small intestine requires SREBP-2 to drive cholesterol synthesis that sustains the intestinal epithelia when uptake of cholesterol from the gut lumen is not available, and provide a unique example of cholesterol auxotrophy expressed in an intact, adult mammal.—Rong, S., J. G. McDonald, and L. J. Engelking. Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine.
AB - SREBP-2 activates transcription of all genes needed for cholesterol biosynthesis. To study SREBP-2 function in the intestine, we generated a mouse model (Vil-BP2/) in which Cre recombinase ablates SREBP-2 in intestinal epithelia. Intestines of Vil-BP2/ mice had reduced expression of genes required for sterol synthesis, in vivo sterol synthesis rates, and epithelial cholesterol contents. On a cholesterol-free diet, the mice displayed chronic enteropathy with histological abnormalities of both villi and crypts, growth restriction, and reduced survival that was prevented by supplementation of cholesterol in the diet. Likewise, SREBP-2-deficient enteroids required exogenous cholesterol for growth. Blockade of luminal cholesterol uptake into enterocytes with ezetimibe precipitated acutely lethal intestinal damage in Vil-BP2/ mice, highlighting the critical interplay in the small intestine of sterol absorption via NPC1L1 and sterol synthesis via SREBP-2 in sustaining the intestinal mucosa. These data show that the small intestine requires SREBP-2 to drive cholesterol synthesis that sustains the intestinal epithelia when uptake of cholesterol from the gut lumen is not available, and provide a unique example of cholesterol auxotrophy expressed in an intact, adult mammal.—Rong, S., J. G. McDonald, and L. J. Engelking. Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine.
KW - Cholesterol/biosynthesis
KW - Fatty acid/synthesis
KW - Niemann-Pick C1-like 1
KW - Organoid
KW - Scap
KW - SREBP
UR - http://www.scopus.com/inward/record.url?scp=85030753891&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030753891&partnerID=8YFLogxK
U2 - 10.1194/jlr.M077610
DO - 10.1194/jlr.M077610
M3 - Article
VL - 58
SP - 1988
EP - 1998
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 10
ER -