Thyroid hormone and dietary carbohydrate induce different hepatic zonation of both "spot 14" and acetyl-coenzyme-A carboxylase: a novel mechanism of coregulation.

The S14 gene encodes a protein found in the nuclei of lipogenic tissues that is induced synergistically by thyroid hormone (T3) and dietary carbohydrate, as are several lipogenic enzymes. In hyperthyroid rats, hepatic expression of S14 protein is zonated. The established association of S14 gene expression with lipogenesis, therefore, prompted a comparison of the zonal distribution of induction of S14 and acetyl-coenzyme-A-carboxylase (ACC), a rate-determining enzyme of fatty acid synthesis, by T3, dietary carbohydrate, and both stimuli together. As determined by immunohistochemistry, liver from chow-fed hypothyroid or euthyroid fasted rats showed essentially no reactivity for either S14 or ACC. Sections from hyperthyroid rats exhibited nuclear staining with anti-S14 antibodies and cytoplasmic reactivity for ACC that was primarily perivenous in both cases. In contrast, sections from euthyroid-fasted animals refed a high carbohydrate, fat-free diet for 3 days exhibited panlobular expression of both antigens. Animals receiving both T3 and high carbohydrate diet refeeding showed increased intensity of staining, compared to the refed group, for both S14 and ACC across the entire lobule. Therefore, in rats consuming normal chow, T3 induced S14 and ACC only in the perivenous zone of the acinus, whereas it further induced these proteins across the entire lobule in the presence of increased carbohydrate intake. Modulation, by the carbohydrate content of the diet, of the fraction of the liver that may express S14 and ACC in response to T3 provides a mechanism for coregulation of the genes involved in hepatic lipid formation. Moreover, the observed cozonation of S14 and ACC as well as the quantitatively similar effects of T3 and dietary carbohydrate on S14, ACC, fatty acid synthetase, and ATP-citrate lyase protein abundance prompt the speculation that S14 acts in the nucleus to promote expression of the genes involved in the lipogenic pathway.