Cells must rapidly adapt to fluctuating environmental conditions to maintain energy and nutrient homeostasis. Altered nutrient storage in cells underlies numerous debilitating metabolic diseases (e.g. obesity, diabetes, atherosclerosis) and has been implicated in cancer, aging and viral lifecycle. To understand the aberrant physiology underlying metabolic diseases it is important to determine the mechanisms that cells use to monitor and functionally adapt to their changing environments.
Nearly every cell type stores energy as triacylglycerol in lipid droplets, an endoplasmic reticulum-derived organelle that is conserved from yeast to humans and is composed of a neutral lipid core encircled by a phospholipid monolayer. Proteins decorating the surface of lipid droplets regulate fat storage and mobilization. For example, specialized proteins called lipases localize to lipid droplets and can degrade triacylglycerol. Controlling the activity of these lipases represents an attractive approach for drug development. Despite the inherent relevance to human diseases, lipid droplets are arguably the least studied and most poorly understood organelle. This disparity stems from an enduring dogma that lipid droplets are inert storage compartments. We now know that lipid droplets are actually extremely dynamic, reacting to environmental stimuli and actively controlling fat storage and cellular energy homeostasis. This recognition has led to a revolution in lipid droplet research, and the scientific community is now confronted with many critical questions: How do lipid droplets form? How are the proteins on the surface of lipid droplets controlled? How does the cell detect nutrient status and communicate this to lipid droplets in order to maintain the balance between storage and utilization of fat? Perhaps most importantly, how can we manipulate lipid droplet function to treat disease?
We recently discovered a putative ubiquitination complex that traffics from the endoplasmic reticulum to lipid droplets under conditions promoting fat storage. One component of this complex, UBXD8, mediates the recruitment of the AAA ATPase p97/VCP and the subsequent inhibition of the rate limiting lipase in lipolysis, ATGL. The inhibition of ATGL activity results in reduced lipolysis and increased lipid droplet size and stability. Our findings raise the exciting possibility of a lipid droplet ubiquitination pathway that is poised to control lipid metabolism by actively remodeling the lipid droplet proteome.
Research in our laboratory seeks to elucidate the role of ubiquitin in the dynamic adaptation of lipid droplet function to changing environments. Our research group also seeks to develop new technologies to identify and study protein complexes that facilitate lipid droplet-organelle tethering and communication. To address these complex questions, our laboratory integrates a unique combination of systems biology (proteomic and functional genomic), chemical biology, and mechanistic cell biology strategies. The long-term goal of our research is to discover fundamental cellular mechanisms controlling lipid homeostasis that can be manipulated as novel therapeutic strategies for the treatment of metabolic diseases.
For more information, visit our website – olzmannlab.com.
Selected Recent Publications
Nguyen, T.B. and Olzmann, J.A.# (2017) Lipid droplets and lipotoxicity during autophagy. Autophagy. Accepted, In Press.
Nguyen, T.B., Louie, S.M., Daniele, J., Tran, Q., Dillin, A., Zoncu, R., Nomura, D.K., Olzmann, J.A.# DGAT1-dependent lipid droplet biogenesis protects mitochondrial function during starvation-induced autophagy. Developmental Cell. 42, 9–21.
Bersuker, K. and Olzmann, J.A.# Establishing the lipid droplet proteome: Mechanisms of lipid droplet protein targeting and degradation. BBA - Molecular and Cell Biology of Lipids (Accepted, In press).
Hwang, J., Walczak, C.P., Shaler, T.A., Olzmann, J.A., Zhang, L., Elias, J.E., Kopito, R.R. (2017) Characterization of protein complexes of the endoplasmic reticulum associated degradation E3 ubiquitin ligase Hrd1. J. Biol. Chem. 292, 9104-9116.
Bateman, L.A., Nguyen, T.B., Roberts, A.M., Miyamoto, D.K., Ku, W.M., Huffman, T.R., Petri, Y., Heslin, M.J., Contreras, C.M., Skibola, C.F., Olzmann, J.A.#, Nomura, D.K.# (2017) Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in Reticulon 4 that impairs ER morphology and cancer pathogenicity. Chem. Comm. (advanced online pub.). PMID: 28352901.
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. Mol. Biol. Cell (28), 270-284. PMID: 27881664.
Stevenson, J., Huang, E.Y., Olzmann, J.A.# (2016) Endoplasmic reticulum-associated degradation and lipid homeostasis. Annu. Rev. Nutr. 36:17.1–17.32. PMID: 27296502.
Riley, B.E., Olzmann, J.A.# (2015) A polyubiquitin chain reaction: Parkin recruitment to damaged mitochondria. PLOS Genet. 11(1), e1004952. PMID: 25612006.