LGND just came out with another paper using mouse models to show that rexinoids such as Targretin actually lower triglyceride levels:
Arterioscler Thromb Vasc Biol 1998 Feb;18(2):272-276
RXR agonists activate PPARalpha-inducible genes, lower triglycerides, and raise HDL levels in vivo.
Mukherjee R, Strasser J, Jow L, Hoener P, Paterniti JR Jr, Heyman RA
Department of Pharmacology, Ligand Pharmaceuticals, Inc, San Diego, Calif. 92121, USA. mukherjee@ligand.com
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 PPARalpha activators and are used in the
treatment of hyperlipidemia. We show that the RXR ligand LGD1069 (Targretin), like gemfibrozil, can activate the
PPARalpha/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 PPARalpha 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.
PMID: 9484993, UI: 98143524 |
