Timothy F. Osborne

Professor, Molecular Biology and Biochemistry
School of Biological Sciences

PH.D., University of California, Los Angeles

Phone: (949)824-2979, 3211
Fax: (949) 824-8551
Email: tfosborn@uci.edu

University of California, Irvine
3244 McGaugh Hall
Mail Code: 3900
Irvine, CA 92697

picture of Timothy F. Osborne

Regulation of gene expression by nutrient regulators; especially cholesterol and fatty acids
URL darwin.bio.uci.edu/~osborne/TOindex.html
The focus of our research is on how fundamental processes of gene regulation are used in the control and management of metabolic homeostasis. Our primary studies are in mammalian lipid metabolism and the two main lipids in mammalian cells are fatty acids and sterols.
In one major area, we study how dietary and metabolic fluctuations alter flux of acetyl CoA into either cholesterol or fatty acids. A major decision point for this is at the gene expression level where changes in mRNA levels result in changes in the concentration of key enzymes in the two pathways to alter acetyl CoA flux accordingly. There is a family of transcriptional regulatory proteins, the sterol regulatory element binding proteins (SREBPs) that control the pathway choices and we are studying the molecular details in how the SREBPs sense the need to shift the flux in response to changing metabolic conditions.
A major difference between the cholesterol and fatty acid synthesis pathways is that the energy and carbon used to make fatty acids can be efficiently re-captured through fatty acid oxidation whereas the synthesis of cholesterol is a metabolic dead end. Because cholesterol cannot be reconverted to acetyl CoA, mammals have evolved a pathway that converts the hydrophobic cholesterol into the more hydrophilic bile acids to eliminate excess cholesterol from the system. In the conversion of cholesterol to bile acids, the rate-controlling enzyme is cholesterol 7-alpha hydroxylase (CYP7A1). Bile acid biosynthesis occurs exclusively in the mammalian liver and is highly regulated at the transcriptional level by both a feed-forward mechanism that senses cholesterol and a feedback mechanism through bile acids. We have uncovered novel aspects of this regulatory process that also couple bile acid regulation to glucose metabolism and growth factor signaling.
Publications Seo, Y.K., Chong H.K., Infante, A.M., Im, S.-S., Xie X., and T. F. Osborne 2009. Genome-wide Analysis of SREBP-1 Binding in Mouse Liver Chromatin Reveals a Preference For Promoter Proximal Binding to a New Motif. Proc. Natl. Acad. Sci. USA In Press
  Im, S.-S., Hammond, L.E., Yousef L., Nugas-Selby C, Shin D.-J., Seo Y.K. , Fong L.G., Young S. Y. and T. F. Osborne. SREBP-1a Regulates Hepatic Fatty Acid Partitioning by Activating Acetyl-Coenzyme A Carboxylase-2. 2009 Mol. Cell. Biol. In Press
  Seo, Y.K., Jeon, T.I., Zhu, B., and T. F. Osborne 2009. Regulation of Steroid 5-alpha reductase type 2 (Srd5a2) by Sterol Regulatory Element Binding Protein-2 . Experimental Cell Research In Press
  Shin, D.-J., and T. F. Osborne. 2009. FGF15/FGFR4 integrates growth factor signaling
with hepatic bile acid metabolism and insulin action J Biol Chem 284, 11110-20
  Jeon, T.I., Zhu, B., Larson, J.L., and Osborne, T.F. (2008). SREBP-2 Regulates Gut Peptide Secretion Through Intestinal Bitter Taste Receptor Signaling in Mice. J. Clin. Invest. 118 3693-700
  Bennett, M.K., Seo, Y.-K., Datta, S., Shin, D.-J., and Osborne, T.F. (2008). Selective Binding of SREBP isoforms and Co-Regulatory Proteins to Promoters for Lipid Metabolic Genes in Liver. J Biol Chem 283, 15628-15637
Graduate Programs Cell Biology

Mechanisms of Gene Expression


Link to this profile http://www.faculty.uci.edu/profile.cfm?faculty_id=2701
Last updated 07/21/2009