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Vol. 59, Issue 2, 170-176, February 2001

Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity

Peter J. A. Davies, Stacey A. Berry, Gregory L. Shipley, Robert H. Eckel, Nathalie Hennuyer, Diane L. Crombie, Kathleen M. Ogilvie, Julia Peinado-Onsurbe, Catherine Fievet, Mark D. Leibowitz, Richard A. Heyman, and Johan Auwerx

Department of Integrative Biology and Pharmacology (P.D., S.B., G.S.), University of Texas School of Medicine, Houston, Texas; Department of Medicine (R.E.), University of Colorado School of Medicine, Denver, Colorado; Institut National de la Sante et de la Recherche Medicale (N.H., C.F.), Institut Pasteur, Lille, France; Ligand Pharmaceuticals (D.C., K.O., M.L., R.H.), San Diego, California; Department of Biochemistry and Molecular Biology (J.P.-O.), University of Barcelona, Spain; and Institut 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

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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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