RXR agonists activate PPARalpha-inducible genes, lower triglycerides, and raise HDL levels in vivo.
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.
Mukherjee
R
R
Department of Pharmacology, Ligand Pharmaceuticals, Inc, San Diego, Calif. 92121, USA. mukherjee@ligand.com
Strasser
J
J
Jow
L
L
Hoener
P
P
Paterniti
J R
JR
Heyman
R A
RA
D042962:Acyl-CoA Oxidase; D000818:Animals; D000077610:Bexarotene; D008076:Cholesterol, HDL / Q000097:blood*; D004338:Drug Combinations; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010088:Oxidoreductases / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D014280:Triglycerides / Q000097:blood*
D008076:Cholesterol, HDL; D004338:Drug Combinations; D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014280:Triglycerides; D000077610:Bexarotene; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D015248:Gemfibrozil