Loss of stearoyl-CoA desaturase activity leads to free cholesterol synthesis through increased Xbp-1 splicing

American Journal of Physiology - Endocrinology and Metabolism - Tập 299 Số 6 - Trang E1066-E1075 - 2010
Chad M. Paton1, James M. Ntambi1,2
1Departments of 1Biochemistry and
2Nutritional Sciences, University of Wisconsin, Madison, Wisconsin

Tóm tắt

Stearoyl-CoA desaturase-1 (SCD-1) is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids (MUFA), which are required for efficient neutral lipid esterification. In the present investigation, we demonstrate that loss of SCD-1 activity increases free cholesterol (FC) content and induces Xbp-1 splicing. We assessed the small molecule SCD-1 inhibitor A939572 on [14C]stearate incorporation into neutral lipids and found its incorporation into triglyceride was unaffected, whereas labeled cholesteryl ester (CE) content was notably diminished. Using either A939572 or liver knockout mice (LKO), we show that loss of SCD-1 activity increases FC levels and activates the liver X receptor (LXR) pathway. Using adenoviral delivery of an active form of X-box binding protein-1 (Xbp-1; Xbp-1s), we show increased sterol synthesis only when cells lack the ability to generate MUFA. The results of the cell-based model were confirmed in LKO mice where fasting-refeeding decreased CE, increased FC, and increased Xbp-1s. On the basis of the present data, we conclude that SCD-1 activity is required for efficient cholesterol esterification to MUFA and that loss of its activity increases Xbp-1s-mediated FC synthesis. It is likely that the accumulation of FC enhances Xbp-1 splicing, induces LXR transcriptional activity, and increases ABCA1 (ATP-binding cassette transporter A1) expression to maintain cholesterol homeostasis.

Từ khóa


Tài liệu tham khảo

10.1152/ajpregu.00862.2006

10.1007/s10549-009-0594-8

10.1016/j.tibs.2007.02.001

10.1074/jbc.M602030200

10.1161/CIRCULATIONAHA.108.793182

10.1016/j.bbrc.2005.05.019

10.1016/S0006-291X(02)00554-5

10.1128/MCB.00077-06

10.1158/0008-5472.CAN-06-0632

10.1007/s11373-007-9160-8

10.1038/ncb1035

10.1194/jlr.M600203-JLR200

10.1152/physiolgenomics.00139.2007

Folch J, 1957, J Biol Chem, 226, 497, 10.1016/S0021-9258(18)64849-5

10.1161/01.ATV.0000101182.89118.E5

10.1074/jbc.M311061200

10.1158/0008-5472.CAN-04-2332

Goldstein JL, 1975, J Biol Chem, 250, 8487, 10.1016/S0021-9258(19)40786-2

10.1128/MCB.00553-09

10.1007/s001090000096

10.1128/MCB.23.21.7448-7459.2003

10.1126/science.1158042

10.1016/j.cardiores.2007.04.012

10.1016/j.cmet.2007.10.014

10.1074/jbc.M005488200

10.1158/0008-5472.CAN-06-4132

10.1074/jbc.M212377200

10.1139/O07-001

10.1074/jbc.M501159200

10.1021/bi0022947

10.1016/j.cmet.2009.04.009

10.1021/bi00304a011

10.1021/bi00462a005

10.1074/jbc.M609490200

10.1074/jbc.M208687200

10.1210/me.2007-0531

10.1016/j.bmcl.2008.06.088

Zhou W, 2003, Cancer Res, 63, 7330

Thông tin
Thông tin xuất bản

American Journal of Physiology - Endocrinology and Metabolism

Tập 299 Số 6

E1066-E1075

Thông tin tác giả