Janardan K. Reddy, MD Magerstadt Professor and Chair Pathology Molecular mechanisms of peroxisome nuclear receptor co-activators Curricula: Cancer Biology Cell Biology E-mail:   jkreddy@northwestern.edu

The major focus of our research is on the biological implications of the highly reproducible pleiotropic effects induced by a variety of structurally diverse chemicals including certain pharmaceutical agents, industrial solvents, phthalate ester plasticizers, herbicides and others. We coined the term peroxisome proliferators to describe these agents. We have made several conceptual advances in our understanding of peroxisome proliferation, among which the following deserve special mention and further detailed mechanistic exploration.

First, the demonstration that the induction of the phenomenon of peroxisome proliferation leads to hypolipidemia led to the suggestion that peroxisome proliferation is linked to lipid metabolism and served as an impetus for the discovery of the peroxisomal b-oxidation system. Second, we discovered the hepatocarcinogenic property of peroxisome proliferators and demonstrated that these agents are non-genotoxic and non-mutagenic. Third, based on the tissue/cell specific responses and the coordinated transcriptional activation of b-oxidation system genes, we hypothesized that peroxisome proliferators exert their action by a receptor-mediated mechanism. Our work on the peroxisome proliferator-binding protein(s) laid the foundation for the identification of peroxisome proliferator activated receptors (PPARs).

Our current research focuses on the characterization of PPAR-mediated signal transduction, including the role of nuclear receptor-coactivators in the induction of cell specific pleiotropic responses. We are using genetically modified animals (transgenic and gene knock-out) to investigate the role of nuclear receptors and cofactors to enhance our understanding of the basic mechanisms of energy utilization, fatty acid oxidation, development of fatty liver, and cancer. Other studies focus on the identification of liver stem cells in pancreas using the copper deficiency rat model of hepatocyte differentiation.

Publications:

Yu, S., Matsusue, K., Kashireddy, P., Cao, W-C., Yeldandi, V., Yeldandi, A. V., Rao, M. S., Gonzalez, F. J., and Reddy, J. K. (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma 1 (PPARgamma1) overexpression.  J. Biol. Chem. 278, 498-505.

Qi, C., Surapureddi, S., Zhu, Y-J., Yu, S., Kashireddy, P., Rao, M. S., and Reddy, J. K. (2003) Transcriptional coactivator PRIP, the peroxisome pproliferator-activated receptor gamma (PPARgamma)-interacting protein, is required for PPARgamma-mediated adipogenesis. J. Biol. Chem. 278, 25281-25284.

Zhu, Y., Kan, L., Qi, C., Kanwar, Y. S., Yeldandi, A. V., Rao, M. S., and Reddy, J. K. (2000) Isolation and Characterization of Peroxisome Proliferator-activated Receptor (PPAR) Interacting Protein (PRIP) as a coactivator for PPAR. J. Biol. Chem. 275, 13510-13516.

Zhu, Y., Qi, C., Jia, Y., Nye, J. S., Rao, M.S., and Reddy, J. K. (2000) Deletion of PBP/PPARBP, the Gene for Nuclear receptor Coactivator Peroxisome Proliferator-activated Receptor-binding Protein, Results in Embryonic Lethality. J. Biol. Chem. 275, 14779-14782.

Hashimoto, T., Fujita, T., Usuda, N., Cook, W., Qi, C., Peters, J. M., Gonzalez, F. J., Yeldandi, A. V., Rao, M. S., and Reddy, J. K. (1999) Peroxisomal and Mitochondrial Fatty Acid b-Oxidation in Mice Nullzygous for Both Peroxisome Proliferator-activated Receptor a and Peroxisomal Fatty Acyl-CoA Oxidase. J. Biol. Chem. 274, 19228-19236.