Steven Berberich, Ph.D., Chair
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Heather A. Hostetler, Ph.D.
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Ph.D.: 2003 Purdue University (W.M. Muir & P. Collodi)
Postdoctoral: Texas A&M University (F. Schroeder & A.B. Kier)
Research Interests:
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.
Selected References:
Hostetler, H.A., A.L. McIntosh, A.D. Petrescu, H. Huang, B.P. Atshaves, E.J. Murphy, A.B. Kier, and F. Schroeder. 2009. Fluorescence techniques used for assessing the impact of binding proteins on acyl-CoA 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 (In press).
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 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-a activity 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 PPARa interactions. Journal of Biomolecular Screening 13: 855-861.
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.
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.
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.
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.
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.
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.
