RXR Agonists Activate PPAR-Inducible Genes, Lower Triglycerides, and Raise HDL Levels In Vivo

From the Departments of Pharmacology (R.M., L.J., P.H., J.R.P.), Drug Safety and Disposition (J.S.), and Retinoid Research (R.A.H.), Ligand Pharmaceuticals, Inc, San Diego, Calif.

Correspondence to Ranjan Mukherjee, Department of Pharmacology, Ligand Pharmaceuticals, Inc, 10255 Science Center Drive, San Diego, CA 92121. E-mail rmukherjee{at}ligand.com

Abstract—Peroxisome proliferator–activated receptors (PPARs) and retinoid X receptors (RXRs) are members of the intracellular receptor superfamily. PPARs bind to peroxisome proliferator–response elements (PPREs) as heterodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPAR activators and are used in the treatment of hyperlipidemia. We show that the RXR ligand LGD1069 (Targretin^(TM)), like gemfibrozil, can activate the PPAR/RXR signal-transduction pathway, including transactivation of the bifunctional enzyme or acyl-CoA oxidase response elements in a cotransfection assay. The activation also occurs in vivo, whereby in rats treated with LGD1069 or gemfibrozil, bifunctional enzyme and acyl-CoA oxidase RNA are induced and the combination of LGD1069 and gemfibrozil leads to a greater induction. Importantly, in hypertriglyceridemic db/db mice treated with RXR or PPAR agonists, triglyceride levels are lowered, and the combination again has significantly greater efficacy. RXR agonists also raise HDL cholesterol levels without changing apoA-I RNA expression. This observation suggests the use of RXR-selective agonists, "rexinoids," either alone or in combination with a fibrate as a new therapeutic approach to treating patients with high triglyceride and low HDL cholesterol levels.

Key Words: RXR • PPAR • rexinoids • hypertriglyceridemia • low HDL

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