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Timothy F. Osborne

Professor, Molecular Biology and Biochemistry School of Biological Sciences

PH.D., University of California, Los Angeles

Research Interests Regulation of gene expression by nutrient regulators; especially cholesterol and fatty acids

Faculty/lab web: http://darwin.bio.uci.edu/~osborne/TOindex.html

Graduate Programs: Cell Biology Mechanisms of Gene Expression Biotechnology

Professional Society ASBMB AAAS

Abstract 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.

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Updated: Last Updated: 07/21/2009