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PK Harris and RF Kletzien
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
The thiazolidinediones are a class of antidiabetic compounds that increase the sensitivity of target tissues to insulin. An earlier study has shown that these compounds enhance the insulin-stimulated differentiation of 3T3-L1 cells and up-regulate expression of differentiation-dependent genes. We have observed that the mRNA encoding the adipocyte fatty acid-binding protein (aFABP) increases shortly after incubation of cells with pioglitazone, a thiazolidinedone analogue. The drug was found to enhance, in a time- and dose-dependent fashion, the expression of a chimeric gene that was constructed by fusing the aFABP promoter upstream of the chloramphenicol acetyltransferase (CAT) gene. To localize the sequence within the promoter that is responsive to pioglitazone, a series of chimeric genes containing sections of the aFABP promoter fused to the CAT gene were analyzed after transfection of 3T3-L1 cells. A section of DNA located at -5.2 kilobases and known to encompass a tissue-specific and differentiation-dependent enhancer element was found to confer responsiveness to the drug. Analysis of sequences in this region of the aFABP promoter by DNA gel retardation assays revealed the presence of a protein in nuclear extracts from drug-treated cells that bound to a specific sequence (ARE-6). The presence of the protein could be demonstrated in differentiated adipocytes, but the protein was present at only low levels in preadipocytes. Treatment of preadipocytes with pioglitazone resulted in the precocious appearance of this protein in nuclear extracts. Multiple copies of the ARE-6 sequence inserted upstream of a heterologous promoter linked to the CAT gene conferred pioglitazone responsiveness. The experiments reported in this study establish that the insulin-sensitizing agent pioglitazone up-regulates expression of the aFABP gene through an element located within a region of DNA responsible for tissue-specific and differentiation-dependent expression of the gene.
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