Statins, fibrates and retinoic acid upregulate mitochondrial acylcarnitine carrier gene expression.
In this study, we investigated the effects of statins, fibrates, 9-cis-retinoic acid and forskolin on the transcription of the mitochondrial carnitine/acylcarnitine carrier (CAC) gene. Statins, fibrates, retinoic acid and forskolin activate luciferase gene reporter activity driven by the -334/+3 bp region of the human CAC promoter containing wild-type (but not mutated) PPRE. These four agents also increase CAC transcript and protein levels. The combinations of statins and fibrates, retinoic acid and fibrates and fibrates and forskolin act synergistically. Mevalonate abolishes the activation of CAC gene expression by statins; the inhibitor of the PKA pathway H89 suppresses the stimulation of CAC gene expression by forskolin. Because CAC is essential for fatty acid beta-oxidation, the above results on the regulation of CAC gene expression provide a novel contribution to the understanding of the hypolipidemic action of statins, fibrates and retinoic acid.
Iacobazzi
Vito
V
Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Bari, Italy.
Convertini
Paolo
P
Infantino
Vittoria
V
Scarcia
Pasquale
P
Todisco
Simona
S
Palmieri
Ferdinando
F
D000077556:Alitretinoin; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002331:Carnitine / Q000031:analogs & derivatives / Q000494:pharmacology; D002995:Clofibric Acid / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026901:Membrane Transport Proteins; D047493:PPAR alpha; C116917:acylcarnitine; D005576:Colforsin; D000077556:Alitretinoin; D002995:Clofibric Acid; D014212:Tretinoin; C120109:SLC25A20 protein, human; D002331:Carnitine