RT Journal Article
SR Electronic
T1 Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 170
OP 176
DO 10.1124/mol.59.2.170
VO 59
IS 2
A1 Peter J. A. Davies
A1 Stacey A. Berry
A1 Gregory L. Shipley
A1 Robert H. Eckel
A1 Nathalie Hennuyer
A1 Diane L. Crombie
A1 Kathleen M. Ogilvie
A1 Julia Peinado-Onsurbe
A1 Catherine Fievet
A1 Mark D. Leibowitz
A1 Richard A. Heyman
A1 Johan Auwerx
YR 2001
UL http://molpharm.aspetjournals.org/content/59/2/170.abstract
AB Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t 1/2 = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.