Howard C. Towle Ph.D.

Current Positions:
Professor and Associate Head
Department of Biochemistry, Molecular Biology and Biophysics

Research Interests:

My research group is exploring the molecular mechanisms by which gene expression is regulated in the mammalian liver in response to nutritional and hormonal signals. The liver plays a central role in coordinating metabolism in the mammal. Hepatocytes experience a constantly changing microenvironment as metabolic fuels and hormones vary in response to nutritional status. In turn, hepatocytes rapidly alter their pattern of gene expression to optimally meet the metabolic needs of the organism.

One model that we are exploring involves the changes that occur in the liver when animals are fed a high carbohydrate diet. This diet leads to elevated expression of genes involved in fatty acid biosynthesis and energy storage. We can mimic these changes in primary cultured hepatocytes by elevating glucose concentrations in the media in the presence of insulin. This system is being used to map the essential regulatory sequences in genes responsive to glucose metabolism. Target genes that we are examining include acetyl-CoA and fatty acid synthase, the central enzymes of fatty acid synthesis; pyruvate kinase, which catalyzes the final step in glycolysis, and the S14 gene, which is involved in control of lipogenesis. These glucose regulatory sequences are in turn used to identify and characterize the transcription factors involved in the regulatory process and to explore how these factors are controlled.

A major goal of this research is to understand how the liver can "sense" increased glucose metabolism in the cytoplasm and transduce this signal into a nuclear event at the level of gene transcription. In addition, hormones act to modulate this pattern of expression. In particular, insulin, glucagon and thyroid hormones play a major role in determining metabolic fuel oxidation or storage in the liver. We are interested in learning how hormonal signals are effectively integrated with nutritional signals to determine final levels of gene expression for enzymes of metabolic importance.

Publications:

Koo, S,-H., Dutcher, A., and Towle, H. C., (2001) "Glucose and Insulin Function through Two Distinct Transcription Factors to Stimulate Expression of Lipogenic Enzyme Genes in Liver," J. Biol. Chem. 276: 9437-9445.

Rufo, C., Teran-Garcia, M. Nakamura, M., Koo, S.-H., Towle, H. C. and Clarke, S. D., (2001) "Involvement of a Unique Carbohydrate Responsive Factor in the Glucose Regulation of Rat Liver Fatty Acid Synthase Gene Expression," J. Biol. Chem. 276: 21969-21975.

O'Callaghan, B. L., Koo, S.-H., Wu, Y., Freake, H. C. and Towle, H. C., (2001) "Glucose Regulation of the Acetyl-CoA Carboxylase Promoter PI in Rat Hepatocytes," J. Biol. Chem. 276: 16033-16039.

Kaytor, E.N., Qian, J., Towle, H.C., Olson, L.K. (2000) An indirect role for upstream stimulatory factor in glucose-mediated induction of pyruvate kinase and S14 gene expression. Mol. Cell. Biochem. 210(1-2):13-21.

Bergad, P.L., Towle, H.C., Berry, S.A. (2000) Yin-yang 1 and glucocorticoid receptor participate in the Stat5-mediated growth hormone response of the serine protease inhibitor 2.1 gene. J. Biol. Chem. 275(11):8114-20.

Koo, S.H., Towle, H.C. (2000) Glucose regulation of mouse S(14) gene expression in hepatocytes. Involvement of a novel transcription factor complex. J. Biol. Chem. 275(7):5200-7.

Magana, M.M., Koo, S.H., Towle, H.C., Osborne, T.F. (2000) Different sterol regulatory element-binding protein-1 isoforms utilize distinct co-regulatory factors to activate the promoter for fatty acid synthase. J. Biol. Chem. 275(7):4726-33.

Bergad, P.L., Towle, H.C., Berry, S.A. (1999) Definition of a high affinity growth hormone DNA response element. Mol. Cell. Endocrinol. 150(1-2):151-9.

Qian, J., Kaytor, E.N., Towle, H.C., Olson, L.K. (1999) Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic beta-cells. Biochem. J. 341( Pt 2):315-22.

Berry, S.A., Bergad, P.L., Stolz, A.M., Towle, H.C., Schwarzenberg, S.J. (1999) Regulation of Spi 2.1 and 2.2 gene expression after turpentine inflammation: discordant responses to IL-6. Am. J. Physiol. 276(6 Pt 1):C1374-82.