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

Cell Biology of Energy Metabolism

The ability of cells to store and utilize energy in a regulated manner is fundamental to life, and abnormalities in energy metabolism play a central role in diseases such as obesity, type 2 diabetes, neurodegeneration, and aging. Our laboratory is interested in cellular energy homeostasis, focusing on three interrelated areas of research: the cell biology of lipid storage, the enzymes of neutral lipid synthesis, and energy metabolism in neurons. Our approaches are basic, emphasizing biochemistry and cellular biology, with specific hypothesis testing in model organisms such as flies and mice.

Nearly all cells have the capacity to store neutral lipids, such as triglycerides and sterol esters, in cytosolic organelles called lipid droplets. Once thought to be inert, lipid droplets are increasingly being recognized as highly dynamic organelles, with diverse functions that include storage of lipids for energy and membranes, transport of lipids within cells, and even possibly as centers of replication for intracellular microorganisms. Despite the importance of lipid droplets, surprisingly little is known their biology. In the past year, we completed a genome-wide screen in Drosophila cells to identify genes involved in lipid droplet formation and utilization. With these newly identified genes in hand, we are studying the molecular processes that govern neutral lipid storage in cells.

The neutral lipids stored in droplets function in a myriad of cellular and physiologic processes. Our group cloned many of the enzymes that synthesize neutral lipids, including those that synthesize sterol esters (ACAT enzymes), triacylglycerols (DGAT enzymes), diacylglycerols (MGAT enzymes), and retinyl esters (ARAT enzymes). We continue to study these enzymes, focusing on their biochemical, cell biological, and physiological functions.

In cells, energy burning occurs in mitochondria. Neurons are particularly rich in mitochondria and mitochondrial dysfunction has been linked to neurodegenerative disease. In a new area of investigation, we are studying mitochondria and neuron function in frontotemporal dementia (FTD), the most common cause of dementia in people under age 65. These studies are being done as part of the Richard’s Investigator Consortium, a new, dynamic and collaborative enterprise aimed at elucidating the basic biology underlying FTD and finding cures or treatments.

Significance
The ability of cells and organisms to store and utilize energy in a regulated manner is fundamental to life, and abnormalities in energy and lipid metabolism play central roles in diseases, such as obesity, type 2 diabetes, and fatty liver disease, and have been increasingly linked to neurodegenerative disease. The fundamental processes of cellular energy metabolism represent a vast unexplored frontier of cell biology. Increased knowledge in this area may identify novel pharmaceutical targets for treating metabolic or neurodegenerative diseases.

 

Approach Our approaches range from basic biochemical and cellular studies to those involving physiology and disease mechanisms in genetically modified mice. In addition to studying mammalian cells, we use genetic approaches in cells from D. melanogaster and S. cerevisiae.

Contributions
Our laboratory identified and cloned many of the genes that encode important enzymes in neutral lipid synthesis and elucidated functions of these enzymes in physiology and disease. For example, we defined the functional roles of ACAT enzymes in systemic cholesterol metabolism and atherosclerosis. We also identified the genes encoding mammalian DGAT, MGAT, and ARAT enzymes and elucidated functional roles for these enzymes in metabolism. Our research has identified several enzymes as potential targets for new therapies.

Examples of current questions we are investigating

• How do cellular lipid droplets form? What genes are involved in regulating this process? What cellular machinery regulates lipid storage and mobilization? Which of these processes in cells play important roles in mammalian physiology or disease?
• How do DGAT enzymes work to generate lipid droplets at the molecular level? How are these enzymes (and triglyceride synthesis) regulated?
• What mechanisms contribute to the resistance to obesity and diabetes in mice lacking DGAT1?
• How does triglyceride deposition in tissues cause tissue dysfunction or “lipotoxicity”?
• What are the physiological functions of MGAT enzymes in whole organisms?
• What are the biological functions of progranulin, and how does progranulin deficiency cause neurodegeneration? Can we use knowledge of progranulin biology to devise strategies to treat neurodegenerative disease?