The prevalence of metabolic diseases has reached epidemic proportions in the United States. In cells, nutrients are stored as triacylglycerol (i.e. at) in lipid droplets (LDs), a conserved endoplasmic reticulum-derived organelle that is consists of a neutral lipid core encircled by a phospholipid monolayer decorated with regulatory proteins. Storage of triacylglycerol in LDs is not only critical for energy production and as a source of membrane precursors, but is central to the pathogenesis of metabolic diseases, such as obesity, diabetes, and cardiovascular disease, and has been linked to aging and cancer. For years LDs were thought of as inert cytoplasmic fat globules and there was little interest among the scientific research community. The recognition that LDs are integrally involved in the etiology of multiple diseases and that LDs are extremely dynamic organelles has paved the way for a burgeoning area of research with the potential to make a significant impact on future treatment strategies for metabolic diseases. LDs fundamentally function as hubs of cellular lipid metabolism, and it is essential that we understand the mechanisms that regulate LD biogenesis and function. Therefore, my proposed research will specifically: 1) Exploit advanced functional genomic strategies to generate a high-density epistatic map of all genes required for LD biogenesis in human cells, 2) Use metabolomics technologies to define the functional impact of ER-LD ubiquitination machinery in LD biogenesis and lipid metabolism, and 3) Utilize proximity labeling proteomic methods to define ER subdomains specialized for LD biogenesis and to determine the temporal dynamics of LD proteome maturation. Integration of these complementary studies will break new ground in cell biology and metabolic disease treatment strategies by advancing our understanding of the mechanisms underlying LD biogenesis and the molecular basis of LD dysfunction in human diseases.

Public Health Relevance

The prevalence of obesity and metabolic diseases has skyrocketed to epidemic proportions in the United States. Lipid droplets are poorly understood organelles that mediate cellular storage of fat and are integral to the development of metabolic diseases. The proposed research will identify new lipid droplet regulatory pathways that can be targeted as part of novel therapeutic treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM112948-02
Application #
8972023
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Nutrition
Type
Earth Sciences/Resources
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Bersuker, Kirill; Olzmann, James A (2018) In Close Proximity: The Lipid Droplet Proteome and Crosstalk With the Endoplasmic Reticulum. Contact (Thousand Oaks) 1:
Li, Zhipeng; Olzmann, James A (2018) A Proteomic Map to Navigate Subcellular Reorganization in Fatty Liver Disease. Dev Cell 47:139-141
Huang, Edmond Y; To, Milton; Tran, Erica et al. (2018) A VCP inhibitor substrate trapping approach (VISTA) enables proteomic profiling of endogenous ERAD substrates. Mol Biol Cell 29:1021-1030
Bersuker, Kirill; Peterson, Clark W H; To, Milton et al. (2018) A Proximity Labeling Strategy Provides Insights into the Composition and Dynamics of Lipid Droplet Proteomes. Dev Cell 44:97-112.e7
Anderson, Kimberly E; To, Milton; Olzmann, James A et al. (2017) Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity. ACS Chem Biol 12:2522-2528
Nguyen, Truc B; Olzmann, James A (2017) Lipid droplets and lipotoxicity during autophagy. Autophagy 13:2002-2003
Bersuker, Kirill; Olzmann, James A (2017) Establishing the lipid droplet proteome: Mechanisms of lipid droplet protein targeting and degradation. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1166-1177
To, Milton; Peterson, Clark W H; Roberts, Melissa A et al. (2017) Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation. Mol Biol Cell 28:270-284
Nguyen, Truc B; Louie, Sharon M; Daniele, Joseph R et al. (2017) DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy. Dev Cell 42:9-21.e5
Bateman, L A; Nguyen, T B; Roberts, A M et al. (2017) Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity. Chem Commun (Camb) 53:7234-7237

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