The effect of thyroid hormone on the chromatin structure and expression of the malic enzyme gene in hepatocytes.

Abstract

Malic enzyme catalyzes the NADP-dependent oxidative decarboxylation of malate to pyruvate and carbon dioxide and is involved in lipogenesis. We have investigated the effect of thyroid hormone on the chromatin structure of the malic enzyme gene in rat liver. Hypersensitivity to DNase I in the immediate 5'-flanking region was altered by T3. T3 stimulation induced hypersensitive sites at -310 base pairs (bp) and -50 bp whereas a hypersensitive site at -170 bp was thyroid hormone independent. Hypersensitive sites identified in the 3'-flanking region showed no change with T3 stimulation. We further characterized expression of the malic enzyme gene as a function of thyroidal state by localizing malic enzyme mRNA in hepatocytes using in situ hybridization histochemistry. In hypothyroid and euthyroid states, two populations of hepatocytes were seen, some with malic enzyme message and others with no detectable message. These differences in malic enzyme gene expression were most evident between groups or regions of hepatocytes. After 10 days of thyroid hormone treatment all hepatocytes demonstrated malic enzyme message. The hypersensitivity results confirm that thyroid hormone stimulation of malic enzyme synthesis occurs in part at the level of transcription, and localization of malic enzyme gene expression suggests this stimulation is accompanied by recruitment of hepatocytes. Hepatocytes may be heterogeneous in their ability to respond to thyroid hormone.