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

Cellular Lipid and Energy Metabolism

The major building blocks of the cell are carbohydrates, proteins, and lipids. Lipids play a crucial and tightly regulated cellular role as the major component of membranes. They are also critical for both cellular and physiological energy homeostasis. Pools of both membrane precursor lipids and energy storage lipids are stored in the lipid droplet, a poorly characterized organelle that has recently been shown to be highly dynamic and involved in many cellular processes. Our lab studies the synthesis of energy storage lipids as well as their storage in and mobilization from lipid droplets.

We use multiple model systems, including yeast, flies, cell culture, and mice, to address key questions in lipiddroplet biology: How is lipid synthesis molecularly coupled to lipid-droplet formation? How are the lipid synthesis enzymes regulated? How are lipids mobilized from lipid droplets? What is the connection between lipid droplets and whole-animal energy homeostasis? Is there heterogeneity in lipid-droplet populations? Key advances in the past year focused on the lipid synthesis enzymes, including the localization of DGAT2 in cells, elucidating the functions of DGAT1 in the skin and the liver, and identifying MGAT2 as a key regulator of intestinal lipid absorption and energy homeostasis in response to dietary fat.

Our lab also investigates the basic mechanisms of frontotemporal dementia (FTD), the most common cause of dementia in people under age 65. As part of the UCSF-based Consortium for FTD Research, we use a variety of model systems, including yeast, cultured neurons, induced pluripotent stem cells, and genetically modified mice, to study how deficiency of the secreted protein progranulin causes FTD.

Recent Publications

Farese Jr., R.V., Walther, T.C. (2009) Lipid droplets finally get a little R‑E‑S‑P‑E‑C‑T. Cell 139:855ñ860.

Shih, M.Y.S., Kane, M.A., Zhou, P., Yen, C.L.E., Streeper, R.S., Napoli, J.L., Farese, Jr., R.V. (2009) Retinol esterification by DGAT1 is essential for retinoid homeostasis in murine skin. J. Biol. Chem. 284:4292ñ4299.

Villanueva, C.J., Monetti, M., Shih, M., Zhou, P., Watkins, S.M., Bhanot, S., Farese, Jr., R.V. (2009) Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology 50:434ñ442.

Walther, T., Farese, Jr., R.V. (2009) The life of lipid droplets. Biochim. Biophys. Acta 1791:459ñ466.

Yen, C.L., Cheong, M.L., Grueter, C., Zhou, P., Moriwaki, J., Wong, J.S., Hubbard, B., Marmor, S., Farese, Jr., R.V. (2009) Deficiency of the intestinal enzyme acyl CoA:monoacylglycerol acyltransferase‑2 protects mice from metabolic disorders induced by high-fat feeding. Nat. Med. 15:442ñ446.

Figure Legend: Lipid synthesis enzymes make triglycerides in the endoplasmic reticulum. Triglycerides are energy storage lipids that are a major constituent of the core of the lipid droplet (LD), a dynamic organelle that likely buds from the endoplasmic reticulum. Adapted from Krahmer, N., Guo, Y., Farese, Jr., R.V., Walther T.C. (2009) SnapShot: Lipid droplets. Cell 139:1024ñ1025.