In our lab we are interested in brain lipid metabolism at both the tissue and cellular level.
Blood-born lipids enter the brain via a dedicated doorway, the blood-brain-barrier. In the brain lipids play an important role in metabolism and signaling. Their specific use depends on many aspects, including brain region, nutritional status and cellular environment. The specifics of lipid uptake into the brain is one research topic in our group.
As the brain controls the systemic energy status and homeostasis, circulating metabolites like lipids are taken up via the tanycycte barrier into specific brain areas, e.g. the hypothalamus, where local lipid sensing occurs. Upon assessment of the metabolic situation, adaptations to systemic metabolism are executed by various brain regions to maintain homeostasis. These processes are a second focus of our group.
It recently became clear, that the underlying mechanisms also involve autophagy, a cellular processes that lipids connect to in many ways. This subject represents our third research field.
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We recently discovered that the hypothalamus differentially processes various lipids. Specific hypothalamic cells, tanycytes and astrocytes, are involved and change in an adaptive manner the local lipid trafficking and local lipid metabolism. We continue to study this delicate interplay of cells and its consequences for the maintenance of body energy homeostasis.
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We offer interesting projects and are always looking for curious, creative and talented people at all levels, including rotation students and graduate students. Please contact Lars by email and send a meaningful CV highlighting your various skills and interests.
Lauterbach, M. A.; Saavedra, V.; Mangan, M. S. J.; Penno, A.; Thiele, C.; Latz, E.; Kuerschner L. 1-Deoxysphingolipids cause autophagosome and lysosome accumulation and trigger NLRP3 inflammasome activiation. Autophagy. 2020, 24, 1-15.
Taylor, J.; Sellin, J.; Kuerschner L.; Krähl, L.; Majlesain, Y.; Förster, I.; Thiele, C.; Weighardt, H.; Weber, E. Generation of immun cell containing adipose organoids for in vitro analysis of immune metabolism. Sci Rep. 2020, 10, 21104.
Diehl, K. L.; Vorac, J.; Hofmann, K.; Meiser, P.; Unterweger, I.; Kuerschner L.; Weighardt, H.; Foerster, I.; Thiele, C. Kupffer cells sense free fatty acids and regulate hepatic lipid metabolism in high fat diet and inflammation. Cells. 2020, 9, 2258.
Gutierrez, E.; Lütjohann, D.; Kerksiek, A.; Fabiano, M.; Oikawa, N.; Kuerschner L.; Thiele, C.; Walter, J. Importance of y-secretase in the regulation of liver X receptor and cellular lipid metabolism. Life Sci Alliance. 2020, 3, e201900521.
Rawish, E.; Nickel, L.; Schuster, F.; Stölting, I.; Frydrychowicz, A.; Saar, K.; Hübner, N.; Othman, A.; Kuerschner, L.; Raasch, W. Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets. J Endocrinol. 2020, 244, 95-110.
Hofmann, K.; Lamberz, C.; Piotrowitz, K.; Offermann, N.; But, D.; Scheller, A.; Al-Amoudi, A.; Kuerschner, L. Tanycytes and a differential fatty acid metabolism in the hypothalamus. Glia. 2017, 65, 231-249.
Hofmann, K.; Rodriguez-Rodriguez, R.; Casals, N.; Scheller, A.; Kuerschner, L. Astrocytes and oligodendrocytes in grey and white matter regions of the brain metabolize fatty acids. Sci Rep. 2017, 7, 10771. doi:10.1038/s41598-017-11103-5.
Alecu, I.; Tedeschi, A.; Behler, N.; Wunderling, K.; Lamberz, C.; Lauterbach, M.; Gaebler, A.; Ernst, D.; Van Veldhoven, P.; Al-Amoudi, A.; Latz, E.; Othman, A.; Kuerschner, L.; Hornemann, T.; Bradke, F.; Thiele, C.; Penno, A. Localization of 1-deoxy-sphingolipids to mitochondria induces mitochondrial dysfunction. proteins. J Lipid Res. 2017, 58, 42-59.
Hofmann, K.; Thiele, C.; Schött, H.F.; Gaebler, A.; Schoene, M.; Kiver, Y.; Friedrichs, S.; Lütjohann, D.; Kuerschner, L. A novel alkyne cholesterol to trace cellular cholesterol metabolism and localization. J Lipid Res. 2014, 55, 583-91.
Thiele, C.; Papan, C.; Hoelper, C.; Kusserow, K.; Gaebler, A.; Schoene, M.; Piotrowitz, K.; Lohmann, D.; Spandl, J.; Stevanovic, A.; Shevchenko, A.; Kuerschner, L. Tracing Fatty Acid metabolism by Click chemistry. ACS Chem. Biol. 2012, 7, 2004-11.
Kuerschner, L.*; Richter, D.; Hannibal-Bach, H.K.; Gaebler, A.; Shevchenko, A.; Eijsing, C.S.; Thiele, C. Exogenous ether lipids predominantly target mitochondria. PLoS One. 2012, 7, e31342. *corresponding author
Fairn, G. D.; Schieber, N. L.; Ariotti, N.; Murphy, S.; Kuerschner, L.; Webb, R. I.; Grinstein, S.; Parton, R. G. High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. J. Cell Biol. 2011, 194, 257-75.
Moessinger, C.; Kuerschner, L.; Spandl, J.; Shevchenko, A.; Thiele, C. Human lysophosphatidylcholine acyltransferase 1 and 2 are located to lipid droplets, where they catalyze the formation of phosphatidylcholine. J. Biol. Chem. 2011, 286, 21330-9.
Spandl, J.; Lohmann, D.; Kuerschner, L.; Moessinger, C.; Thiele, C. Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region. J. Biol. Chem. 2011, 286, 5599-5606.
Fei, W.; Shui, G.; Gaeta, B.; Du, X.; Kuerschner, L.; Li, P.; Brown, A. J.; Wenk, M. R.; Parton, R. G.; Yang, H. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J. Cell Biol. 2008, 180, 473-482.
Gütschow, M.; Kuerschner, L.; Pietsch, M.; Ambrozak, A.; Neumann, U.; Günther, R.; Hofmann, H.-J. Inhibition of cathepsin G by 2-amino-3,1-benzoxazin-4-ones: Kinetic investigations and docking studies. Arch. Biochem. Biophys. 2002 , 402, 180-191.
Kuerschner, L. Untersuchungen zu Cathepsin G-Inhibitoren. Apothekenmagazin. 2000, 10, 8-10.
Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger, K. 2-(Diethylamino)[1,3]oxazin-4-ones as Stable Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1999, 42, 5437-5447.
Affiliated with the lab of Christoph Thiele, we have been interested in cellular organelles commonly associated with the storage of fat, lipid droplets. Although most cells contain lipid droplets, it is adipoytes, the cells of adipose tissue (fat tissue), which are specialized to store most of our energy resources as triglycerides (fat) in their lipid droplets.
The mechanism by which cells pack triglycerides into lipid droplets is poorly understood. The use of polyene lipids developed by the Thiele lab allowed for following triglyceride biosynthesis and the flux of lipids to the lipid droplets in living cells. The underlying mechanisms are of significant importance as their understanding may facilitate the development of treatments for certain lipid storage diseases.
We have discovered that the enzyme Diacylglycerol: AcylCoA-Acyltransferase 2 (DGAT2), which is essential for life and produces triglyceride, is found on lipid droplets and is active there. This finding emphasizes the essential role DGAT2 plays for the process of lipid storage and renders this enzyme a prime target for biomedical research seeking to control this process.
We also used polyene analogues of ether lipids, a lipid class of special importance for the brain, in microscopy tracing experiments. This study has highlighted a role for mitochondria in ether lipid metabolism.
To study cellular lipid metabolism we apply biochemical, spectroscopic, microscopic, cell and molecular biological techniques. Fluorescence microscopy of living cells yields valuable information on dynamic processes, while electron microscopy provides the highest resolution data.
Lipid analogues such as the polyene lipids or alkyne lipids are valuable tools to track cellular lipid metabolism both kinetically and spatially. In our laboratory we have been developing these tools and the respective microscopy routines for high resolution lipid imaging.