Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis.
The nuclear receptor liver X receptor (LXR) alpha, 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 LXRalpha 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 LXRalpha 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 LXRalpha transcripts in cultured primary hepatocytes. Complementary studies where rats and mice were injected with insulin induced LXRalpha mRNA levels and confirmed our in vitro studies. Furthermore, deletion of both the LXRalpha and LXRbeta 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.
Tobin
Kari Anne Risan
KA
Institute for Nutrition Research and Institute of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0316 Oslo, Norway.
Ulven
Stine M
SM
Schuster
Gertrud U
GU
Steineger
Hilde Hermansen
HH
Andresen
Sissel Mahle
SM
Gustafsson
Jan-Ake
JA
Nebb
Hilde Irene
HI
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D015152:Blotting, Northern; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D003609:Dactinomycin / Q000494:pharmacology; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D003609:Dactinomycin; D012313:RNA; D002784:Cholesterol; D003513:Cycloheximide