Robert V. Farese, Jr., MD
Senior Investigator,
Gladstone Institute of Cardiovascular Disease
Professor of Medicine, Biochemistry and Biophysics
University of California, San Francisco
Email: bfarese@gladstone.ucsf.edu
Telephone: 415-734-2000
Fax: 415-355-0960

How do cells synthesize, store, and utilize neutral lipids?

Most cells store neutral lipids, such as triglycerides and sterol esters, in cytosolic organelles called lipid droplets. Once thought to be inert, lipid droplets are clearly dynamic organelles that store lipids for energy and membranes, transport lipids within cells, and even serve as centers of replication for intracellular microorganisms. Despite their importance, little is known about their biology. In the past year, using a genome-wide screen in Drosophila cells, we identified many genes involved in the formation and function of lipid droplets. We have begun to study the role of these genes in cells and flies in order to unravel some of the fundamental mechanisms of lipid droplet formation and utilization. Our approaches emphasize biochemistry and cellular biology and test specific hypotheses in model organisms, such as yeast, flies and mice.

The lipids found within droplets are synthesized by lipid acyl transferase enzymes . We study the biochemical, cell biological, and physiological functions of the enzymes that synthesize triglycerides (DGATs), sterol esters (ACATs), and diacylglycerols (MGATs). We are particularly interested in the relationship of these enzymes to lipid droplet biogenesis.

How does progranulin deficiency lead to neurodegeneration?

Neurodegeneration and neurobiology is a new and growing interest of the laboratory. We are using a variety of model systems, including yeast, cultured neurons, and genetically modified mice, to study the basic mechanisms that underlie frontotemporal dementia (FTD), the most common cause of dementia in people under age 65. Our work focuses on biological signaling pathways linked to progranulin, as haploinsufficiency of this secreted protein almost invariably leads to FTD.

Recent Publications

Guo, Y., Walther, T.C., Rao, M., Stuurman, N., Goshima, G., Terayama, K., Wong, J.S. Vale, R.D., Walter, P., Farese, Jr., R.V. (2008) Functional genomic screen reveals genes involved in lipid droplet formation and utilization. Nature. 453:657-61.

Stone, S.J., Levin, M.C., Zhou, P., Han J., Walther, T.C., and Farese, Jr., R.V. (2008) The endoplasmic reticulum enzyme, DGAT2, is present in mitochondria-associated membranes and possesses a mitochondrial targeting signal that promotes its association with mitochondria. Journal of Biological Chemistry. 284:5352-61.

Walther, T., Farese, Jr., R.V. (2008) The Life of Lipid Droplets. Biochimica et Biophysica Acta. (Epub ahead of print)

Figure Legend: Larger, more dispersed lipid droplets (LDs) in HeLa cells with knockdown (KD) of ARF1. Control cells treated with oleic acid accumulate LDs. In cells with KD of ARF1 (by RNAi) treated with oleate, the LDs appear distinctly different and lipolys