TY - JOUR
T1 - Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis
AU - Biosynthesis, Cholesterol
AU - Tobin, Kari Anne Risan
AU - Ulven, Stine M.
AU - Schuster, Gertrud U.
AU - Steineger, Hilde Hermansen
AU - Andresen, Sissel Mæhle
AU - Gustafsson, Jan Åke
AU - Nebb, Hilde Irene
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2002/3/22
Y1 - 2002/3/22
N2 - The nuclear receptor liver X receptor (LXR) α, an important regulator of cholesterol and bile acid metabolism, was analyzed after insulin stimulation in liver in vitro and in vivo. A time- and dose-dependent increase in LXRα steady-state mRNA level was seen after insulin stimulation of primary rat hepatocytes in culture. A maximal induction of 10-fold was obtained when hepatocytes were exposed to 400 nM insulin for 24 h. Cycloheximide, a potent inhibitor of protein synthesis, prevented induction of LXRα mRNA expression by insulin, indicating that the induction is dependent on de novo synthesis of proteins. Stabilization studies using actinomycin D indicated that insulin stimulation increased the half-life of LXRα transcripts in cultured primary hepatocytes. Complementary studies where rats and mice were injected with insulin induced LXRα mRNA levels and confirmed our in vitro studies. Furthermore, deletion of both the LXRα and LXRβ genes (double knockout) in mice markedly suppressed insulin-mediated induction of an entire class of enzymes involved in both fatty acid and cholesterol metabolism. The discovery of insulin regulation of LXR in hepatic tissue as well as gene targeting studies in mice provide strong evidence that LXRs plays a central role not only in cholesterol homeostasis, but also in fatty acid metabolism. Furthermore, LXRs appear to be important insulin-mediating factors in regulation of lipogenesis.
AB - The nuclear receptor liver X receptor (LXR) α, an important regulator of cholesterol and bile acid metabolism, was analyzed after insulin stimulation in liver in vitro and in vivo. A time- and dose-dependent increase in LXRα steady-state mRNA level was seen after insulin stimulation of primary rat hepatocytes in culture. A maximal induction of 10-fold was obtained when hepatocytes were exposed to 400 nM insulin for 24 h. Cycloheximide, a potent inhibitor of protein synthesis, prevented induction of LXRα mRNA expression by insulin, indicating that the induction is dependent on de novo synthesis of proteins. Stabilization studies using actinomycin D indicated that insulin stimulation increased the half-life of LXRα transcripts in cultured primary hepatocytes. Complementary studies where rats and mice were injected with insulin induced LXRα mRNA levels and confirmed our in vitro studies. Furthermore, deletion of both the LXRα and LXRβ genes (double knockout) in mice markedly suppressed insulin-mediated induction of an entire class of enzymes involved in both fatty acid and cholesterol metabolism. The discovery of insulin regulation of LXR in hepatic tissue as well as gene targeting studies in mice provide strong evidence that LXRs plays a central role not only in cholesterol homeostasis, but also in fatty acid metabolism. Furthermore, LXRs appear to be important insulin-mediating factors in regulation of lipogenesis.
UR - http://www.scopus.com/inward/record.url?scp=0037155935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037155935&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109771200
DO - 10.1074/jbc.M109771200
M3 - Article
C2 - 11781314
AN - SCOPUS:0037155935
VL - 277
SP - 10691
EP - 10697
JO - The Journal of biological chemistry
JF - The Journal of biological chemistry
SN - 0021-9258
IS - 12
ER -