Heather A. Hostetler, Ph.D.
Office: 056 Diggs Lab
Lab: 025 Diggs Lab
Ph.D.: 2003 Purdue University (W.M. Muir & P. Collodi)
Postdoctoral: Texas A&M University (F. Schroeder & A.B. Kier)
My research interests are focused on nuclear receptor regulation in energy homeostasis. Although we know a variety of nuclear receptors must function both synergistically and antagonistically together in order to maintain a healthy body, how these receptors interact with each other and their environment remains to be discovered. My current NIH funding (R00) focuses on the peroxisome proliferator-activated receptor alpha (PPARa) and its heterodimeric partners, the retinoid X receptor (RXR) and the liver X receptor (LXR), to determine how dietary nutrients (lipids and sugars) can lead to possible mis-regulation such as that seen in instances of diabetes. This work combines both molecular and biochemical techniques to elucidate protein-ligand interactions, protein-protein interactions, and ligand trafficking in living cells.
PPARa plays a central role in energy homeostasis by initiating transcription of multiple genes in fatty acid and glucose metabolism, while concomitantly down-regulating genes in insulin signaling. In liver, PPARa induces transcription of many genes involved in fatty acid degradation by b-oxidation, fatty acid uptake and transport, and lipoprotein metabolism. RXR and LXR have similar functions: regulating control of a different set of genes involved in energy homeostasis. Thus, these nuclear receptors are responsible for controlling a number of lipid metabolic proteins that may contribute to obesity, diabetes, lipotoxicity, and subsequent cardiovascular disorders. Previous work in our lab and by others has shown that unsaturated fatty acids, as well as saturated and unsaturated fatty acid metabolites, are endogenous ligands of PPARa. The presence of these ligands leads to PPARa activation and initiation of fatty acid metabolism. More recently, we have shown that glucose is also an endogenous ligand of PPARa, and that the presence of certain sugars can alter not only PPARa activity, but also its ability to interact with lipids. These discoveries have suggested that nuclear receptors may function as nutrient sensors; sensing what nutrients are available and utilizing them as an energy source. We are currently working to determine: (i) How PPARa determines its choice of heterodimeric partners, (ii) What this choice means in terms of overall gene regulation, (iii) What happens to cause the improper regulation seen in diseased states, and (iv) What kind of compounds might function as potential therapeutics to reverse the detrimental effects of such diseased states.
Oswal, D.P., M. Balanarasimha, J.K. Loyer, F.L. Soman, S.D. Rider, Jr., and H.A. Hostetler. 2013. Divergence between human and murine peroxisome proliferator-activated receptor alpha ligand specificities. Journal of Lipid Research (In press).
Kolawole, A.O., P. Sharma, R. Yan, K.J.E. Lewis, H.A. Hostetler, and K.J.D.A. Excoffon. 2012. The PDZ1 and PDZ3 domains of MAGI-1 regulate the eight-exon isoform of the coxsackievirus and adenovirus receptor. Journal of Virology 86: 9244-9254.
Kiselyuk, A., S.-H. Lee, S. Farber-Katz, M. Zhang, S. Athavankar, T. Cohen, A.B. Pinkerton, M. Ye, P. Bushway, A.D. Richardson, H.A. Hostetler, M. Rodriguez-Lee, L. Huang, B. Spangler, L. Smith, J. Higginbotham, J. Cashman, H. Freeze, P. Itkin-Ansari, M.I. Dawson, F. Schroeder, Y. Cang, M. Mercola, and F. Levine. 2012. HNF4aantagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chemistry and Biology 19: 806-818.
Schroeder, M.E., H.A. Hostetler, F. Schroeder, and J. Ball. 2012. Elucidation of the rotavirus NSP4-caveolin-1 and cholesterol interactions using synthetic peptides. Journal of Amino Acids 2012: 575180, 16.
Hostetler, H.A., D. Lupas, Y. Tan, J. Dai, M.S. Kelzer, G.G. Martin, G. Woldegiorgis, A.B. Kier, and F. Schroeder. 2011. Acyl-CoA binding proteins interact with the acyl-CoA binding domain of mitochondrial carnitine palmitoyl transferase I. Molecular and Cellular Biochemistry 355:135-148.
Hostetler, H.A., M. Balanarasimha, H. Huan, M.S. Kelzer, A. Kaliappan, A.B. Kier, and F. Schroeder. 2010. Glucose regulates fatty acid binding protein interactions with lipids and PPARa. Journal of Lipid Research 51: 3103-3116.
Hostetler, H.A., A.L. McIntosh, A.D. Petrescu, H. Huang, B.P. Atshaves, E.J. Murphy, A.B. Kier, and F. Schroeder. 2010. Fluorescence methods to assess the impact of lipid binding proteins on ligand-mediated activation of gene expression. In Lipid-Mediated Signaling: Methods in Signal Transduction, [eds.] E.J. Murphy and T.A. Rosenberger. CRC Press, Taylor and Francis Group, New York, pp. 299-348.
Hostetler, H.A., A.L. McIntosh, B.P. Atshaves, S.M. Storey, H.R. Payne, A.B. Kier, and F. Schroeder. 2009. Liver type fatty acid binding protein (L-FABP) directly interacts with peroxisome proliferator-activated receptor-ain cultured primary hepatocytes. Journal of Lipid Research 50: 1663-1675.
McIntosh, A.L., B.P. Atshaves, H.A. Hostetler, H. Huang, J. Davis, O.I. Lyuksyutova, D. Landrock, A.B. Kier, and F. Schroeder. 2009. Liver type fatty acid binding protein (L-FABP) gene ablation reduces nuclear ligand distribution and peroxisome proliferator-activated receptor-aactivity in cultured primary hepatocytes. Archives of Biochemistry and Biophysics 485: 160-173.
Hostetler, H.A., L.R. Syler, L.N. Hall, G. Zhu, F. Schroeder, and A.B. Kier. 2008. A novel high-throughput screening assay for putative anti-diabetic agents through PPARainteractions. Journal of Biomolecular Screening 13: 855-861.
Hostetler, H.A., H. Huang, A.B. Kier, and F. Schroeder. 2008. Glucose directly links to lipid metabolism through high-affinity interaction with peroxisome proliferator-activated receptor a. Journal of Biological Chemistry 183: 2246-2254.
Hostetler, H.A., A.B. Kier, and F. Schroeder. 2006. Very-long-chain and branched-chain fatty acyl-CoAs are high affinity ligands for the peroxisome proliferator-activated receptor a(PPARa). Biochemistry 45: 7669-7681.
Hostetler, H.A., A.D. Petrescu, A.B. Kier, and F. Schroeder. 2005. Peroxisome proliferator-activated receptor a(PPARa) interacts with high affinity and is conformationally responsive to endogenous ligands. Journal of Biological Chemistry 280: 18667-18682.