Associate Professor of Molecular Therapeutics*
*and of Nutritional Sciences & Toxicology

Full Directory Information

Research Interests

The biology of cellular lipid homeostasis is a challenging frontier in science and medicine, and many outstanding questions remain. The importance of this field is underscored by the dysregulation of lipid metabolism in numerous diseases, including prevalent metabolic diseases and cancer. Our lab exploits interdisciplinary strategies that integrate systems-level discovery methods (e.g. CRISPR-Cas9 screens and proteomics), chemical biology tools, and cell biology approaches to advance our understanding of the mechanisms that regulate lipid homeostasis. We are particularly interested in understanding the regulation of neutral lipid storage organelles called lipid droplets and the pathways that prevent lipotoxicity. Our primary objectives include elucidating: 1) the regulation and functions of lipid droplets, 2) the mechanisms that govern lipid droplet proteome composition and dynamics, 3) the molecular underpinnings that mediate organelle crosstalk in lipid homeostasis, and 4) the cellular responses that combat lipotoxicity such as oxidative lipid damage and ferroptosis. Ultimately, we aim to tackle difficult and complex problems in biology, catalyze progress, and translate our basic discoveries into novel therapeutics.

Current Projects

Lipid droplet biogenesis and regulation
Lipid droplets are dynamic neutral lipid (i.e. fat and sterol esters) storage organelles that function as hubs of lipid metabolism, providing an “on demand” source of fatty acids that can be used for energy, membrane biogenesis, and lipid signaling pathways. Lipid droplets form at the endoplasmic reticulum (ER) in a process involving the deposition of neutral lipids between the leaflets of the ER, the phase separation of neutral lipids into a lipid aggregate or lens, and the emergence of the lipid droplet into the cytoplasm from the outer leaflet of the ER. The precise mechanisms by which a monolayer organelle emerges from a bilayer organelle are incompletely understood. Does this occur at specific ER subdomains? Is this driven by proteins and/or lipid changes? The mature lipid droplet can be degraded by lipolysis or through a selective autophagic pathway known as lipophagy. How these pathways are regulated under different conditions and in different cell types remains to be determined. Furthermore, alterations in lipid droplet abundance are associated with a wide variety of diseases. For example, the accumulation of large hepatic lipid droplets is the pathological hallmark of fatty liver disease and mutations in certain genes (e.g. TM6SF2 and PNPLA3) are associated with increased risk of fatty liver. Human genetics may provide insights into the cellular mechanisms that regulate lipid droplet biogenesis and turnover. We aim to leverage genetic screens and proteomic approaches to discover the mechanisms that control lipid droplet biology and to exploit this knowledge to develop novel therapeutic approaches.

Establishing and remodeling the lipid droplet proteome
The functions of lipid droplets are controlled by the proteins that decorated the lipid droplets surface. These proteins are collectively as the lipid droplet proteome and include lipid metabolic enzymes (acyl transferases and lipases) as well as signaling scaffold proteins that monitor and integrate the nutrient status of the cell. We are especially interested in how the lipid droplet proteome is established and regulated (see https://www.dropletproteome.org/). Under certain conditions some lipid droplet proteins are targeted for proteolysis by ER-associated degradation (ERAD), which mediates the ubiquitin and proteasome dependent degradation of proteins from the early secretory pathway. What machinery (e.g. E3 ligase) target lipid droplet proteins for proteasomal clearance? Can proteins be ubiquitinated and extracted for proteasomal degradation directly from the lipid droplet? Does ubiquitin-dependent degradation of lipid droplet proteins contribute to the regulation of lipid droplet functions during metabolic state fluctuations?

Inter-organelle crosstalk and lipid homeostasis
Lipid droplets do not exist in isolation, but instead are in constant contact with many organelles in the cell. These contacts enable transfer of lipids and proteins, such as the transfer of fatty acids for β-oxidation in mitochondria. Our recent findings have identified multiple examples of inter-organelle communication. We found that the degradation of select lipid droplet proteins in the ER though ERAD, regulates their levels on lipid droplets. In addition, we discovered an unexpected protective role for DGAT1-dependent lipid droplets during autophagy, in which they served as lipid buffers sequestering fatty acids and preventing lipotoxic damage to other organelles. Our current studies aim to identify and characterize the physical complexes that mediate lipid droplet association with other organelles in the cell. How are these contacts regulated? Are they impacted by the metabolic state of the cell? Furthermore, how extensive is the role of lipid droplets in preventing lipotoxicity? Under what physiological conditions is this important?

Mechanisms of oxidative lipid damage and lipotoxic cell death
Lipotoxicity generally refers to the deleterious effects that lipids can have on cellular homeostasis and function. Accumulation of different types of lipids can induce distinct forms of lipotoxicity. For example, free fatty acids can induce ER stress by incorporation into ER lipids or can cause mitochondrial damage through incorporation into acylcarnitines. We and others have found that lipid droplets can prevent fatty acid toxicity under certain conditions by sequestering fatty acids as triacylglyercerol. Some lipids play direct roles in cell death pathways, such as the association of ceramide in apoptotic signaling and oxidatively damaged phospholipids in the non-apoptotic cell death pathway known as ferroptosis. By leveraging genome wide CRISPR-Cas9 synthetic lethal screens we recently identified a new pathway that suppresses ferroptosis through the generation of reduce coenzyme Q10, which can function as a potent lipophilic antioxidant. Targeting this pathway is sufficient to sensitize cancer cells to ferroptosis inducers, raising the possibility that this pathway can be therapeutically targeted. We are interested in leveraging similar genetic and cell biology approaches to understand the mechanisms of different types of lipotoxicity and the cellular factors that protect against these forms of damage.
 

Selected Publications

Bersuker, K., Hendricks, J., Li, Z., Magtanong, L., Ford, B., Tang, P.H., Roberts, M.A., Tong, B., Maimone, T.J., Zoncu, R., Nomura, D.K., Bassik, M.C., Dixon, S.J., Olzmann, J.A. (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 575(7784):688-692.

Olzmann, J.A. and Carvalho, P. (2019) Dynamics and functions of lipid droplets. Nature Review of Cell and Molecular Biology. 20(3): 137-155.

Huang, E.Y.*, To, M.*, Tran, E., Dionisio, L., Cho, H.J., Baney, K.L.M., Pataki, C.I., Olzmann, J.A. (2018) A VCP inhibitor substrate trapping approach (VISTA) enables proteomic profiling of endogenous ERAD substrates. Molecular Biology of the Cell. 29(9), 1021-1030.

Bersuker, K., Peterson, C.W., To, M., Sahl, S.J., Savikhin, V., Grossman, E.A., Nomura, D.K., Olzmann, J.A. (2018) A proximity labeling strategy provides insights into the composition and dynamics of lipid droplet proteomes. Developmental Cell. 44, 97-112.

Nguyen, T.B., Louie, S.M., Daniele, J., Tran, Q., Dillin, A., Zoncu, R., Nomura, D.K., Olzmann, J.A. (2017) DGAT1-dependent lipid droplet biogenesis protects mitochondrial function during starvation-induced autophagy. Developmental Cell. 42, 9–21.

To, M.*, Peterson, C.W.*, Roberts, M.A., Counihan, J.L., Wu, T.T., Forster, M.S., Nomura, D.K., Olzmann, J.A. (2017) Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation. Molecular Biology of the Cell. (28), 270-284.

Last Updated 2020-08-11