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.
N1 - Funding Information:
This work was supported by National Institutes of Health Grant HL-20948. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. L.J.E. was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant 5K08DK102652. Manuscript received 5 May 2017 and in revised form 12 June 2017. Published, JLR Papers in Press, June 19, 2017 DOI https://doi.org/10.1194/jlr.M077610
Publisher Copyright:
Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
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 - SREBP
KW - Scap
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U2 - 10.1194/jlr.M077610
DO - 10.1194/jlr.M077610
M3 - Article
C2 - 28630260
AN - SCOPUS:85030753891
VL - 58
SP - 1988
EP - 1998
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 10
ER -