RXR AGONISTS ACTIVATE PPAR-ALPHA-INDUCIBLE GENES, LOWER TRIGLYCERIDES, AND RAISE HDL LEVELS IN-VIVO

Peroxisome proliferator-activated receptors (PPARs) and retinoid X rec eptors (RXRs) are members of the intracellular receptor superfamily. P PARs bind to peroxisome proliferator-response elements (PPREs) as hete rodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPAR alpha act ivators and are used in the treatment oi hyperlipidemia. We show that the RXR ligand LGD1069 (Targetin(TM)), like gemfibrozil, can activate the PPAR alpha/RXR signal-transduction pathway, including transactivat ion oi the bifunctional enzyme or acyl-CoA oxidase response elements i n a cotransfection assay. The activation also occurs in vivo, whereby in rats treated with LGD1069 or gemfibrozil, bifunctional enzyme and a cyl-CoA oxidase RNA are induced and the combination of LGD1069 and gem fibrozil leads to a greater induction, Importantly, in hypertriglyceri demic db/db mice treated with RXR or PPAR alpha agonists, triglyceride levels are lowered, and the combination again has significantly great er efficacy. RXR agonists also raise HDL cholesterol levels without ch anging apoA-I RNA expression. This observation suggests the use of RXR -selective agonists, ''rexinoids,'' either alone or in combination wit h a fibrate as a new therapeutic approach to treating patients with hi gh triglyceride and low HDL cholesterol levels.