Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone.
Pioglitazone, a thiazolidinedione (TZD) derivative, is an antidiabetic agent that improves hyperglycaemia and hyperlipidaemia in obese and diabetic animals via a reduction in hepatic and peripheral insulin resistance. The TZDs including pioglitazone have been identified as high affinity ligands for peroxisome proliferator-activated receptor (PPAR) gamma. The selectivity of pioglitazone for the human PPAR subtypes has not been reported, thus, we investigated the effect of pioglitazone on the human PPAR subtypes. Transient transactivation assay showed that pioglitazone is a selective hPPARgamma1 activator and a weak hPPARalpha activator. Binding assay indicated that the transactivation of hPPARgamma1 or hPPARalpha by pioglitazone is due to direct binding of pioglitazone to each subtype. Furthermore, pioglitazone significantly increased the apoA-I secretion from the human hepatoma cell line HepG2.
Sakamoto
J
J
Discovery Research Laboratories IV, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kimura
H
H
Moriyama
S
S
Odaka
H
H
Momose
Y
Y
Sugiyama
Y
Y
Sawada
H
H
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D001629:Bezafibrate / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D002839:Chromans / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D000077205:Pioglitazone; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D016632:Apolipoprotein A-I; D002839:Chromans; D007004:Hypoglycemic Agents; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077288:Troglitazone; D011345:Fenofibrate; D000077205:Pioglitazone; D001629:Bezafibrate