De novo expression of uncoupling protein 3 is associated to enhanced mitochondrial thioesterase-1 expression and fatty acid metabolism in liver of fenofibrate-treated rats.
Uncoupling protein 3 (UCP3) is a member of the mitochondrial carrier superfamily, preferentially expressed in skeletal muscle. Its function is not fully understood and it is debated whether it uncouples oxidative phosphorylation as does UCP1 in brown adipose tissue. Recent evidences suggest a role for UCP3 in the flux of fatty acids in and out mitochondria and their utilization in concert with mitochondrial thioesterase-1 (MTE-1). In fact, mice overexpressing muscle UCP3 also show high levels of MTE-1. Fenofibrate is a hypolipidemic drug that prevents body weight gain in diet-induced obese rats and enhances lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Because fatty acids and fenofibrate stimulate PPARs and in turn UCP3, we investigated whether UCP3 expression might be induced 'de novo' in situations of increased hepatic mitochondrial fatty acid utilization caused by a combined effect of a high-fat diet and fenofibrate treatment. We also investigated whether Mte-1 expression and beta-oxidation were affected. We show here that Ucp3 is induced in liver of fenofibrate-treated rats at the mRNA and protein level. Expression was restricted to hepatocytes and was unevenly distributed in the liver. No increase in cell proliferation, inflammatory or fibrotic responses was found. Mte-1 expression and mitochondrial beta-oxidation were upregulated. Thus, Ucp3 can be transactivated in tissues where it is normally silent and fenofibrate can attain this effect in liver. The data demonstrate that UCP3 is involved in fatty acid utilization and support the notion that UCP3 and MTE-1 are linked within the same metabolic pathway.
Lanni
Antonia
A
Department of Life Sciences, Second University of Naples, Caserta, Italy.
Mancini
Francesco P
FP
Sabatino
Lina
L
Silvestri
Elena
E
Franco
Renato
R
De Rosa
Gaetano
G
Goglia
Fernando
F
Colantuoni
Vittorio
V
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007473:Ion Channels; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D024101:Mitochondrial Proteins; D010084:Oxidation-Reduction / Q000187:drug effects; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation / Q000187:drug effects; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D010170:Palmitoyl-CoA Hydrolase; D011345:Fenofibrate