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SHR Neuro Cancer Cardio Metab Microb Lipid

Hormonal regulation of lipolysis

Abstract: Lipases play a key role in regulation of whole body energy homeostasis. Control of lipolysis is important for energy partitioning and balance and maintains the size of fat depots in the body. Dysregulation of lipolytic activities affects lipid absorption, mobilization and transport, and is causative for lipid-related diseases. The release of free fatty acids is dependent on the lipolysis of stored triacylglycerol which is tightly controlled by neural regulation and several hormones to meet energy demands. Molecular mechanisms of this regulation are poorly understood but post-translational modification, protein interactions, protein localizations and access of lipases to their substrates appear to play a major role. Phosphorylation of hormone sensitive lipase, the lipolysis regulator perilipin 1 and more recently also adipose triglyceride lipase (ATGL) have been described on various sometimes controversial sites by different sometimes unknown kinases. Regulations and functions of described sites, however, are poorly understood. Moreover, no information is yet available on regulation of other important players, such as monoglyceride lipase or the ATGL regulators comparative gene identification 58 (CGI-58/ABHD-5) and G0/G1 switch gene 2.
We have established an analytical platform for activity-based discovery, detection, profiling and imaging of lipolytic enzymes in intact cells and tissues. In our activity-based proteomic screens we have repeatedly detected active isoforms of lipases suggesting that they are posttranslationally modified. Moreover, we have recently discovered a novel post translational modification of CGI-58 by protein kinase A. Previous work by others and us points thus towards the existence of lipolytic complexes and post translational modification of the involved proteins, warranting a comprehensive screen for novel regulators of lipolysis.
The major objective of the proposed project Hormonal regulation of lipolysis is to provide a better understanding of the regulation of lipid homeostasis. We will perform in vitro kinase assays to search for novel substrates of known kinases among known lipolytic proteins and protein regulators, investigate the (phospho)proteomic effects of hormonal regulation on lipolytic complexes in murine and human tissues, and functionally analyze selected novel potential regulators of lipolysis (i.e. novel phosphosites, including our novel CGI-58 phosphosite, and/or novel interacting proteins).
Although many protein functions appear to be conserved in humans and mice there is growing evidence for important interspecies differences, especially in complex diseases caused by genetic and environmental factors, which cannot be easily reproduced in model organisms. While activity-based probes were already successfully employed to identify novel lipolytic enzymes in mouse liver and adipose tissue homogenates, this study will for the first time shed light on the lipolytic proteome of human adipose tissues in situ directly at enzymatic activity level. Combined with standard quantitative (phospho)proteomic profiling relevant regulators of lipolytic activities will be identified and might offer entry points for future therapies.

Project Leader:: Birner-Grünberger Ruth

Duration:: 01.09.2013-31.08.2016

Programme:: Einzelprojekt

Type of Research: basic research

Staff: Birner-Grünberger, Ruth, Project Leader; Kohlbacher, Julia, Co-worker; Schittmayer-Schantl, Matthias, Co-worker

MUG Research Units: Diagnostic and Research Institute of Pathology

Funded by: FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria

Project results published: > Spatially Resolved Activity-based Proteomic Profil... Mol Cell Proteomics. 2020; 19(12):2104-2114; > Myristic acid induces proteomic and secretomic cha... J Proteomics. 2018; 181(7):118-130; > Quantification of cellular folate species by LC-MS... Anal Chem. 2018;; > Deletion of Adipose Triglyceride Lipase Links Tria... J Proteome Res. 2018; 17(4):1415-1425; > The role of protein-phosphorylation in lipolysis... APRS 2017; Sep 6-8; Graz, AUSTRIA. 2017.; > Mitochondrial fragmentation in fatty liver... APRS 2017; Sep 6-8; Graz, AUSTRIA. 2017.; > Adipose triglyceride lipase (ATGL) promotes oncoge... APRS 2017; Sep 6-8; Graz, AUSTRIA. 2017.; > Resolution Ladder for High-Resolution Mass Spectro... Anal Chem. 2017; 89(18):9611-9615; > Crystal structure of the Saccharomyces cerevisiae ... Biochim Biophys Acta. 2016; 1861(5):462-470; > Tracking Protein S-Fatty Acylation with Proteomics... Chembiochem. 2016; 17(16):1488-1490; > Cleaning out the Litterbox of Proteomic Scientists... J Proteome Res. 2016; 15(4):1222-1229; > Regulation of lipolysis by phosphorylation... Amino Acids. 2015; 47(8):1607--14th International Congess on Amino Acids, Peptides and Proteins; Aug 3-7; Vienna.; > Changes in one carbon metabolism that follow the l... Austrian Proteomics Research Symposium; AUG 26-28, 2015; Maria Gugging, AUSTRIA. 2015.; > CGI-58/ABHD5 is phosphorylated on Ser239 by protei... J Lipid Res. 2015; 56(1):109-121; > Conformational plasticity and ligand binding of ba... J Biol Chem. 2013; 288(43):31093-31104; > Global protein function analysis in basic medical ... Modern Analytical Chemistry; Nov 29, 2013; Vienna, Austria. 2013.; > Novel technologies applied to the study of lipolys... BHF CENTRE of RESEARCH EXCELLENCE ADIPOSE TISSUE WORKSHOP; Dec 12-13, 2013; Edinburgh, UK. 2013.