Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity
- Peter J. A. Davies1,
- Stacey A. Berry1,
- Gregory L. Shipley1,
- Robert H. Eckel2,
- Nathalie Hennuyer3,
- Diane L. Crombie4,
- Kathleen M. Ogilvie4,
- Julia Peinado-Onsurbe5,
- Catherine Fievet3,
- Mark D. Leibowitz4,
- Richard A. Heyman4 and
- Johan Auwerx6
- 1Department of Integrative Biology and Pharmacology (P.D., S.B., G.S.), University of Texas School of Medicine, Houston, Texas;2Department of Medicine (R.E.), University of Colorado School of Medicine, Denver, Colorado; 3Institut National de la Sante et de la Recherche Medicale (N.H., C.F.), Institut Pasteur, Lille, France; 4Ligand Pharmaceuticals (D.C., K.O., M.L., R.H.), San Diego, California; 5Department of Biochemistry and Molecular Biology (J.P.-O.), University of Barcelona, Spain; and 6Institut de Génétique et Biologie Moleculaire et Cellulaire (J.A.), Institut National de la Sante et de la Recherche Medicale/Centre National de la Recherche Scientifique/ULP, Illkirch, France
Abstract
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 (t1/2 = 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.
Footnotes
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Send reprint requests to: Dr. Peter J. A. Davies, Dept. of Integrative Biology and Pharmacology, University of Texas School of Medicine, P.O. Box 20708, Houston, TX 77225. E-mail:peter.j.davies{at}uth.tmc.edu
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This work was supported by grants from Ligand Pharmaceuticals, the National Institutes of Health (DK26356), the Fondation de France, the European Union (Grant QLG1-CT-1999-00674), CNRS, INSERM, and Hôpitaux Universitaires de Strasbourg. J.A. and C.F. are research directors with CNRS and INSERM, respectively.
- Abbreviations:
- RA
- retinoic acid
- LDL
- low-density lipoprotein
- VLDL
- very-low-density lipoprotein
- LPL
- lipoprotein lipase
- RAR
- retinoic acid receptor
- RXR
- retinoid X receptor
- PPAR
- peroxisome proliferator-activated receptor
- ZDF
- Zucker diabetic fatty
- DMEM
- Dulbecco's modified Eagle's medium
- HDL
- high-density lipoprotein
- TTNPB
- (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid
- Act D
- actinomycin D
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- Received July 18, 2000.
- Accepted October 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
