Metabolic effects of rexinoids: Tissue-specific regulation of lipoprotein lipase activity

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 t his observation, we have studied the effects of rexinoids on triglyceride m etabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid inc rease in serum triglyceride levels. LG268 has no effect on hepatic triglyce ride production but suppresses postheparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished p eripheral processing of plasma very low density lipoproteins particles. Tre atment of diabetic rats with rexinoids suppresses skeletal and cardiac musc le but not adipose tissue LPL activity. This effect is independent of chang es in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surfa ce (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 i nhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest t hat skeletal muscle may be an important target of rexinoid action. In addit ion, these data underscore that the metabolic consequences of RXR activatio n are distinct from either retinoic acid receptor or peroxisome proliferato r-activated receptor activation.