Research Interests   Nutritional and Hormonal Regulation of Mammalian Gene Expression

Obesity is a metabolic disorder often associated with insulin resistance and type 2 diabetes that is increasing at an alarming rate throughout the world. The incidence of non-alcoholic fatty liver disease is rising concordantly with obesity and may contribute to the pathogenesis of insulin resistance and other complications of the metabolic syndrome. Dietary carbohydrate (e.g., high fructose corn syrup) can contribute to obesity and fatty liver disease through the process of de novo lipogenesis - the conversion of simple carbohydrate into triglycerides. To better understand the pathways promoting de novo lipogenesis, we have been studying the glucose-stimulated activation of lipogenic enzyme gene expression in liver and in cultured primary hepatocytes. Genes that respond to glucose contain a distinct regulatory element designated the carbohydrate response element (ChoRE). ChoREs have been found within regulatory regions of the pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase genes. Recently, ChREBP or Carbohydrate Response Element Binding Protein was implicated in glucose-stimulated gene activation. We found that ChREBP acts as a heteromeric complex with another nuclear factor known as Max-like factor X (Mlx). ChREBP and Mlx form stable complexes that associate with the ChoREs of several lipogenic enzyme genes. A dominant negative form of Mlx that blocks binding of ChREBP to this site concomitantly abrogates the entire program of lipogenic enzyme gene induction by glucose. This includes genes encoding enzymes of glycolysis, fatty acid biosynthesis, NADPH generation, fatty acid maturation, triglyceride synthesis and lipoprotein formation. We are focusing our current research efforts on unraveling the mechanism by which ChREBP and Mlx are regulated by glucose in the liver and their overall physiological role in metabolic regulation. The positioning of ChREBP/Mlx at the interface between carbohydrate and fat metabolism suggests a potential role in contributing to fatty liver disease and the metabolic dysregulation that can result from this condition.

Tsatsos, N. G., Davies, M. N., O’Callaghan, B. L. and Towle, H. C., Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP, Biochem. J. 411: 261-270 (2008) [PMID: 18215143]

Davies, M. N., O’Callaghan, B. L. and Towle, H. C., Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity, J. Biol. Chem. 283: 24029-24038 (2008) [PMID: 18591247]

Ma, L., Tsatsos, N. G. and Towle, H. C., Direct Role of ChREBP/Mlx in Regulating Hepatic Glucose-responsive Genes, J. Biol. Chem. 280: 12019-12027, (2005). http://www.jbc.org/cgi/reprint/280/12/12019

Towle, H.C., Glucose as a Regulator of Eukaryotic Gene Transcription, Trends Endocrinol. Metab. 16: 489-494, (2005).

Tsatsos, N.G. and Towle, H.C., Glucose Activation of ChREBP in Hepatocytes Occurs via a Two-Step Mechanism, Biochem. Biophys. Res. Commun. 340: 449-456, (2006).

Ma, L., Robinson, L. N. and Towle, H. C., ChREBP/Mlx Is the Principal Mediator of Glucose-induced Gene Expression in the Liver, J. Biol. Chem. 281: 28721-28730 (2006) http://www.jbc.org/cgi/reprint/281/39/28721

Ma, L., Sham, Y. Y., Walters, K. J. and Towle, H. C., A Critical Role for the Loop Region of the Basic Helix-Loop-Helix/Leucine Zipper Protein Mlx in DNA Binding and Glucose-regulated Transcription, Nuc. Acids Res. 35: 35-44 (2007) http://nar.oxfordjournals.org/cgi/screenpdf/35/1/35