The goal of the SFB-LIPOTOX is to unify relevant research forces in Graz on one theme: Lipotoxicity. The research consortium defines lipotoxicity as the anomalous uptake, generation, and activity of lipid derivatives mediating adverse, lipotoxic effects including dysregulation of metabolic pathways, cell- and organelle dysfunction, and cell death. To investigate lipotoxicity as a pathological basis of human disease and to discover molecular processes that can prevent lipotoxicity, we propose to identify and characterize the molecular and cellular mechanisms activated by lipotoxic substances. Genomic, proteomic, and lipidomic technology will be utilized to discover novel lipotoxic pathways. Mutant mouse and yeast models will be analyzed to elucidate the mechanisms that cause the production of toxic lipid compounds, lead to cellular dysfunction, and induce apoptosis or other forms of cell death. It is evident that such a broad scientific aim requires a conceptual strategy that supersedes the singular focus of individual research groups, and that ensures effective exchange of ideas, expertise and resources. The SFB program of the FWF provides the appropriate framework for a dynamic and interactive research consortium embedded in a number of related project programs. We expect our findings to contribute to the identification of valid targets for disease intervention.
Titel: F 3018 Abhydrolase Domain Containing 15 (ABHD15) - a Key Factor in Lipid Metabolism and Apoptosis, Contact: Bogner-Strauß (01.01.2015-31.03.2017)
The objective of this project is to investigate the role of ABHD15 in lipolysis, apoptosis, and lipid signaling. The mammalian ABHD family consists of at least 19 proteins and belongs to the superfamily of proteins with an /-hydrolase fold. ABHD5 (also known as CGI-58, the co-activator of adipose triglyceride lipase) is a prominent member of this protein family and biochemically and functionally characterized, whereas the functions of other family members, including ABHD15, are largely unknown. ABHD15 is mainly expressed in white and brown adipose tissues, liver, and to a much lower extent in cardiac and skeletal muscle. Physiological conditions with high plasma levels of free fatty acids like fasting, high fat diet, genetic obesity, or aging cause reduced ABHD15 expression. Upon insulin stimulation, ABHD15 has been shown to bind and thereby regulate protein levels of phosphodiesterase 3B (PDE3B) and might thus modulate protein kinase A (PKA)-dependent pathways including lipolysis and glucose metabolism. We have recently demonstrated that ABHD15 is a direct and functional target of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) and that stable silencing of ABHD15 in 3T3-L1 cells strongly impairs adipogenesis. Additionally, we observed that knockdown of Abhd15 in preconfluent 3T3-L1 cells leads to impaired cell proliferation due to increased apoptosis. Together, these data suggest that ABHD15 is a key factor in the regulation of lipolysis and apoptosis, and therefore plays a crucial role in lipotoxic signaling. In the proposed research aims we will:
1) Use gain- and loss-of-function approaches in vitro to get detailed mechanistic insight into the interaction of PDE3B and ABHD15 as nodal point between insulin signaling and the downstream cAMP-related pathways such as PKA-mediated lipolysis. Further, we aim to elucidate the potential role of ABHD15 in regulating glucose uptake.
2) Investigate the physiological consequences of ABHD15 deficiency in vivo by characterizing ABHD15 knockout (ko) mice. Specifically, we will focus on the effects of ABHD15 deficiency on lipid metabolism, lipid signaling, and apoptosis.
Titel: F 3006 Toxicity of oxidized phospholipids in macrophages, Contact: Hermetter, (01.04.2007 - 31.03.2011)
Toxicity of oxidized phospholipids in macrophages
The SFB LIPOTOX creates an excellent scientific environment and provides a large spectrum of technical expertise. Extensive collaborations within this consortium will allow fast progress and a successful outcome of this project. The findings of this proposal will provide insight into ABHD15-regulated pathways and will reveal how ABHD15 impacts lipid metabolism and lipid signaling pathways.