Research Interests

A) Cell-Specific Control of Thyroid Hormone Action. One project in the laboratory is to understand the mechanisms involved in the regulation of thyroid hormone action. Thyroid hormones play an important role in the control of growth, development, and intermediary metabolism in all vertebrates. The active form of thyroid hormone, 3,5,3'-triiodothyronine (T3), exerts physiological effects by interacting with nuclear receptors that modulate the transcription of specific genes. Nuclear T3 receptors specifically bind to DNA sequences that confer T3-mediated regulation on promoter activity. Using the malic enzyme gene as a model, we have shown that alterations in the activity of the nuclear T3 receptor are responsible for differences in thyroid hormone responsiveness between hepatocytes and fibroblasts. We have identified several cisacting elements in the malic enzyme gene that enhance T3 responsiveness in hepatocytes but not in fibroblasts. We are currently characterizing the nuclear proteins that interact with these regulatory sequences and analyzing the mechanism by which they modulate nuclear T3 receptor activity.

B) Regulation of Lipogenic Enzyme Expression. Another research interest is to determine the mechanisms involved in the nutritional control of the acetyl-CoA carboxylase gene. Acetyl-CoA carboxylase catalyzes the rate-limiting step in the de novo synthesis of fatty acids and plays a crucial role in controlling this process in vertebrates. The activity of acetyl-CoA carboxylase is regulated by nutritional and hormonal factors. Feeding animals a high-carbohydrate, low-fat diet stimulates the rate of synthesis of acetyl-CoA carboxylase. Diet-induced changes in acetyl-CoA carboxylase synthesis are mimicked in primary cultures of hepatocytes by manipulating the concentrations of thyroid hormone, glucose, insulin and glucagon in the culture medium. We have recently shown that the effects of diet and hormones on acetyl-CoA carboxylase expression are mediated primarily by changes in the transcription rate of the acetyl-CoA carboxylase gene. We are currently characterizing the cis-acting sequences and trans-acting factors that mediate the effects of nutrients and hormones on acetyl-CoA carboxylase transcription.

Recent Publications

Hillgartner, F. B., Chen, W., and A. G. Goodridge. (1992) Overexpression of the thyroid hormone receptor-a in avian cell lines. Effects on expression of the malic enzyme gene are selective and cell-specific. J. Biol. Chem. 267: 12299-12306.

Hillgartner, F. B., Salati, L. M., and Goodridge, A. G. (1995) Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. Physiol. Rev. 75:47-76.

Hillgartner, F. B., Charron, T., and Chesnut, K. A. (1996) Alterations in nutritional status regulate acetyl-CoA carboxylase expression in avian liver by a transcriptional mechanism. Biochem. J. 319, 263-268.

Hillgartner, F. B., Charron, T., and Chesnut, K. A. (1997) Triiodothyronine stimulates and glucagon inhibits transcription of the acetyl-CoA carboxylase gene in chick embryo hepatocytes. Glucose and insulin amplify the effect of triiodothyronine. Arch. Biochem. Biophys. 337, 159-168.

Fang, X., and Hillgartner, F. B. Cell-specific regulation of transcription of the malic enzyme gene. Characterization of cis-acting elements that modulate nuclear T3 receptor activity. Submitted.

Hillgartner, F. B., and Charron, T. Regulation of expression of the gene for acetyl-CoA carboxylase by fatty acids. Submitted.

Contact: E-mail: fbhill@wvnvms.wvnet.edu Phone: 304-293-7751 Fax: 304-293-6846