Malic enzyme gene in chick embryo hepatocytes in culture: clofibrate regulates responsiveness to triiodothyronine.

In chick embryo hepatocytes, triiodothyronine (T3) causes a 30- to 40-fold increase in malic enzyme activity when added between 1 and 3 days, but has no effect when added between 5 and 7 days in culture. This transcription-mediated decline in T3 responsiveness is partially reversed by corticosterone (Roncero, C. and A. G. Goodridge, 1992. Arch. Biochem. Biophys. 295: 258-267). Clofibrate also reversed the decline in responsiveness to T3, and did so in the absence of an increase in binding of T3 to nuclear receptors. The effects of clofibrate and corticosterone were additive, suggesting different mechanisms. The responsiveness of a gene to a specific agent depends on specific regulatory sequences of DNA in that gene. When 5.8 kb of the 5'-flanking DNA of the malic enzyme gene was linked to the chloramphenicol acetyltransferase (CAT) gene and transfected into hepatocytes, T3 stimulated CAT activity. Responsiveness of CAT activity to T3 decreased with time, and this decrease was partially reversed by clofibrate. The T3 responses of cells transfected with various chimeric DNAs that contained T3 response elements (T3REs) of the malic enzyme gene or synthetic consensus T3REs also were increased by clofibrate. The results suggest that clofibrate regulates expression of a metabolite or a protein factor which, in turn, influences function of the T3 receptor.