Heather Hostetler, PhD
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 focus is 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, including 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.
Recent work in our lab has also shown that a single amino acid difference between PPARa from mouse and human can lead to differences in their ability to interact with dietary nutrients. These differences can lead to downstream changes in gene regulation and may alter overall energy metabolism. This work suggests that amino acid mutations within the human population could have strong effects on these receptors and may lead to diseased states such as cardiovascular disease, atherosclerosis, and diabetes.
- Oswal, D.P., G.M. Alter, S.D. Rider, Jr., and H.A. Hostetler. 2014. A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor a. Journal of Molecular Graphics and Modeling 51: 27-36. Abstract
- Balanarasimha, M., A.M. Davis, F.L. Soman, S.D. Rider, Jr., and H.A. Hostetler. 2014. Ligand regulated heterodimerization of peroxisome proliferator-activated receptor alpha with liver X receptor alpha. Biochemistry 53: 2632-2643. Abstract
- Karumuri, A.K., A.A. Maleszewski, D.P. Oswal, H.A. Hostetler, and S.M. Mukhopadhyay. 2014. Fabrication and characterization of antibacterial nanoparticles supported on hierarchical substrates. Journal of Nanoparticle Research 16: 2346.
- McIntosh, A.L., A.D. Petrescu, H.A. Hostetler, A.B. Kier, and F. Schroeder. 2013. Liver-type fatty acid binding protein interacts with hepatocyte nuclear factor-4a. FEBS Letters 587: 3787-3791. Abstract
- Oswal, D.P., M. Balanarasimha, J.K. Loyer, S. Bedi, 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 54: 2354-2365. Abstract JLR article
- Karumuri, A., D.P. Oswal, H.A. Hostetler, and S.M. Mukhopadhyay. 2013. Silver nanoparticles attached to porous carbon substrates: robust materials for chemical-free water disinfection. Materials Letters 109: 83-87.
- 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. PMC article
- 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. HNF4a antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chemistry and Biology 19: 806-818. PMC article
- 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. PMC article
- 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. PMC article
- 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. PMC article
- Atshaves, B.P., G.G. Martin, H.A. Hostetler, A.L. McIntosh, A.B. Kier, and F. Schroeder. 2010. Liver fatty acid binding protein and obesity. Journal of Nutritional Biochemistry 21: 1015-1032. PMC article
- 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-a in cultured primary hepatocytes. Journal of Lipids Research 50: 1663-1675. PMC article
- 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-a activity in cultured primary hepatocytes. Archives of Biochemistry and Biophysics 485: 160-173. PMC article
- 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 PPARa interactions. Journal of Biomolecular Screening 13: 855-861. PMC article
- Martin, G.G., H.A. Hostetler, A.L. McIntosh, S.E. Tichy, B.J. Williams, D.H. Russel, J.M. Berg, T.A. Spencer, J.A. Ball, A.B. Kier, and F. Schroeder. 2008. Structure and function of the sterol carrier protein-2 (SCP-2) N-terminal pre-sequence. Biochemistry 47: 5915-5934. PMC article
- Petrescu, A.D., H. Huang, H.A. Hostetler, F. Schroeder, and A.B. Kier. 2008. Structural and functional characterization of a new recombinant histidine-tagged acyl coenzyme A binding protein (ACBP) from mouse. Protein Expression and Purification 58: 184-193. PMC article
- 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. PMC article
- Schroeder, F., A.D. Petrescu, H. Huang, B.P. Atshaves, A.L. McIntosh, G.G. Martin, H.A. Hostetler, A. Vespa, D. Landrock, K. Landrock, H.R. Payne, and A.B. Kier. 2008. Role of fatty acid binding proteins in modulating nuclear receptors. Lipids 43: 1-17.
- R.D. Parr, G.G. Martin, H.A. Hostetler, M.E. Schroeder, K.D. Mir, A.B. Kier, J.M. Ball, F. Schroeder. 2007. A new N-terminal recognition domain in caveolin-1 interacts with sterol carrier protein-2 (SCP-2). Biochemistry 46: 8301-8314. PMC article
- 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. PMC article
- Schroeder, F., H. Huang, H.A. Hostetler, A.D. Petrescu, R. Hertz, J. Bar-Tana, and A.B. Kier. 2005. Stability of fatty acyl-coenzyme A thioesters ligands of hepatocyte nuclear factor-4a and peroxisome proliferator-activated receptor-a. Lipids 40: 559-568.
- 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. PMC article
- Hostetler, H.A., P. Collodi, R.H. Devlin, and W.M. Muir. 2005 Improved phytate phosphorus utilization by Japanese medaka transgenic for the Aspergillus niger phytase gene. Zebrafish 2: 19-31
- Hostetler, H.A. Transgenic Fish by Electroporation. Information Systems for Biotechnology (ISB) News Report, May 2004
- Rider, Jr., S.D., M.R. Hemm, H.A. Hostetler, H.-C. Li, C. Chapple, and J. Ogas. 2004. Metabolic profiling of the Arabidopsis pkl mutant reveals selective depression of embryonic traits. Planta 219: 489-499. PMC article
- Hostetler, H.A., S.L. Peck, and W.M. Muir. 2003. High efficiency production of germ-line transgenic Japanese medaka (Oryzias latipes) by electroporation with direct current-shifted radio frequency pulses. Transgenic Research 12: 413-424.