Systems Biology and Metabolism
Large-scale, quantitative, high-quality data sets often form the basis for discovery. We employ techniques such as mass spectrometry, genome-perturbations screens, and high-content microcopy to generate hypotheses or models for biological processes. For example, our laboratory uses powerful state-of-the-art proteomics and lipidomics to obtain global insights into the regulation of lipid metabolism. Once we have identified important regulatory circuitry, we combine our ability to determine abundances of molecules with methodologies, such as live cell imaging, to generate hypotheses and investigate these dynamic processes on the cellular and physiological level.
Selected Recent Publications
Song J, Mizrak A, Lee CW, Cicconet M, Lai ZW, Lu CH, Mohr SE, Farese RV Jr**, Walther TC**. (2022). Identification of two pathways mediating protein targeting from ER to lipid droplets. Nat Cell Biol. 24(9):1364-1377.
Mejhert N, Gabriel KR, Frendo-Cumbo S, Krahmer N, Song J, Kuruvilla L, Chitraju C, Boland S, Jang DK, von Grotthuss M, Costanzo MC, Rydén M, Olzmann JA, Flannick J, Burtt NP, Farese RV Jr**, Walther TC**. (2022) The Lipid Droplet Knowledge Portal: A resource for systematic analyses of lipid droplet biology. Dev Cell. 57(3):387-397.
Christiano R*, Arlt H*, Kabatnik S, Mejhert N, Lai ZW, Farese RV Jr**, Walther TC**. (2020) A systematic protein turnover map for decoding protein degradation. Cell Rep. 33(6):108378.
Mejhert N, et al. (2020) Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression. Mol Cell. 77(6):1251-1264.e9.
Piccolis, M., Bond, L., et al. (2019). Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids. Mol Cell. 74(1), 32-44.e8.
Li, Z., et al. (2018). Global Analyses of Selective Insulin Resistance in Hepatocytes Caused by Palmitate Lipotoxicity. Mol Cell Proteomics. 17(5), 836-849.
Fröhlich, F., et al. (2016). Proteomic and phosphoproteomic analyses of yeast reveal the global cellular response to sphingolipid depletion. Proteomics. 16(21), 2759-2763.
Currie, E et al. (2014) High confidence proteomic analysis of yeast LDs identifies additional droplet proteins and reveals connections to dolichol synthesis and sterol acetylation. J. Lipid Res. 55(7):1465-1477.
Krahmer, N et al. (2013) Protein correlation profiles identify lipid droplet proteins with high confidence. Mol. Cell Proteomics 12(5):1115-1126
Lysosomal Lipid Metabolism and Neurodegeneration
Increasing evidence points to the contribution of endosome and lysosome dysfunction in the development of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We study metabolism of the endo-lysosomal system, focusing on how it regulates the metabolism of membrane lipids, in particular sphingolipids. We are testing the hypothesis that accumulation of toxic sphingolipids and glycosphingolipids leads to neurodegeneration in diseases such as ALS, FTD, and other neurodegenerative diseases.
Selected Recent Publications
Boland, S. Swarup S, Ambaw Y.A, Richards R.C, Fischer A.W, Singh S. Aggarwal G, Spina S, Nana A.L, Grinberg L.T, Seeley WW, Surma MA, Klose C, Paulo JA, Nguyen AD, Harper JW, Walther TC**, Farese RV Jr.** (2022) Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis. Nat Comm. 13(1):5924
Petit CS.et al. (2020) Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration. Proc Natl Acad Sci U S A. 117(19):10565-10574
Nguyen AD. et al. (2018) Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay. Proc Natl Acad Sci U S A. 115(12): E2849-E2858.
Fröhlich, F. et al. (2015) The GARP complex is required for cellular sphingolipid homeostasis. Elife 4:e08712.
Martens, L.H. et al. (2012) Progranulin deficiency promotes neuroinflammation and neuronal loss following toxin-induced injury. J. Clin. Invest. 122(11): 3955-3959.
Biology of Cellular Energy Metabolism
The supply and demand for metabolic energy in cells fluctuates. Therefore, organisms have evolved mechanisms to store metabolic energy. The most efficient way cells store energy is in the form of highly reduced carbons found in triacylglycerols (TGs). Although energy storage is inherently beneficial, exceeding the capacity for cells to store TGs has led to metabolic diseases such as obesity, diabetes, and fatty liver disease.
We study how cells store metabolic energy as TGs in organelles called lipid droplets (LDs). Specifically, we study the molecular basis for how cells synthesize TGs, how cells form LDs, how proteins target to LDs, and how TGs are utilized to meet energetic demands.
Our laboratory studies these fundamental questions using a wide range of cutting-edge interdisciplinary approaches, including biophysical, biochemical, and cell biological methods. We also investigate the physiological importance of these lipid storage mechanisms in various cellular and animal models, including models of metabolic diseases or cancer.
Selected Recent Publications
Song J, Mizrak A, Lee CW, Cicconet M, Lai ZW, Lu CH, Mohr SE, Farese RV Jr**, Walther TC**. (2022). Identification of two pathways mediating protein targeting from ER to lipid droplets. Nat Cell Biol. 24(9):1364-1377.
Arlt H, Sui X, Folger B., Adams C, Chen X, Remme R, Hamprecht F.A, DiMaio F, Liao M, Goodman J.M, Farese RV Jr**, Walther TC**. (2021) Seipin forms a flexible cage at lipid droplet formation sites. Nat Struct Mol Biol. 29(3): 194-202.
Olarte MJ, Kim S, Sharp ME, Swanson JMJ, Farese RV Jr**, Walther TC**. (2020) Determinants of endoplasmic reticulum-to-lipid droplet protein targeting. Dev Cell. 54(4):471-487.e7
Sui X, Wang K, Gluchowski NL, Elliott SD, Liao M, Walther TC**, Farese RV Jr**. (2020) Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme. Nature. 581(7808):323-328.
Mejhert N, et al. (2020) Partitioning of MLX-Family Transcription Factors to Lipid Droplets Regulates Metabolic Gene Expression. Mol Cell. 77(6):1251-1264.e9.
Gluchowski NL, et al. (2019) Hepatocyte Deletion of Triglyceride-Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice. Hepatology. 70(6):1972-1985