Molecular mechanisms mediating ZAG signaling

Zinc-a2-glycoprotein (ZAG) is present in serum and exhibits high homology to antigen-presenting proteins of the major histocompatibility complex class I (MHC-I). MHC-I proteins present peptide-antigens to cytotoxic T lymphocytes. In contrast, ZAG does not bind peptide-antigens and appears to possess a completely different function. ZAG causes weight loss in animal models and is increased in chronic diseases which are associated with cachexia. Currently it is believed that ZAG has a regulatory function in energy metabolism by stimulation fatty acid mobilization from adipose tissue. However, the molecular mechanism of ZAG action is controversial. To investigate ZAG signaling, we were searching for protein interaction partners of ZAG and identified a protein playing a central role in the immune system. Our observations suggest that ZAG acts as anti-inflammatory molecule which possibly can explain its lipolytic effects in adipose tissue. The objective of the proposed investigations is to investigate ZAG signaling on the molecular level and in animal models. The clarification of this process could strongly improve our knowledge of metabolic processes contributing to the pathogenesis of cachexia.

MOLECULAR MECHANISMS MEDIATING ZINC-2-GLYCOPROTEIN SIGNALING Zinc-2-glycoprotein (ZAG) is present in serum and exhibits high homology to antigen-presenting proteins of the major histocompatibility complex class I (MHC-I). MHC-I proteins present peptide-antigens to cytotoxic T lymphocytes. In contrast, ZAG does not bind peptide-antigens and appears to possess a completely different function. Clinical studies indicate that ZAG is decreased in obesity and increased in chronic diseases which are associated with weight loss (cachexia). Currently it is believed that ZAG has a regulatory function in energy metabolism by stimulation of lipolysis in adipose tissue leading to fatty acid mobilization. However, the molecular mechanism of ZAG action on adipose tissue is controversial. The objective of the proposed investigations was to investigate ZAG signaling on the molecular and cellular level. In particular, we focused on preliminary data indicating an interaction of ZAG with semicarbazide-sensitive aminoxidase (SSAO) leading to suppression of SSAO activity. SSAO is highly expressed on adipocytes and plays an important role in inflammatory processes. This enzyme participates in the degradation of biological active amine and can promote the invasion of leucocytes in inflamed tissues. Metabolic disorders like obesity and cachexia are characterized by chronic inflammation. Therefore, if ZAG indeed regulates SSAO activity, this observation could substantially improve our understanding of metabolic processes leading to inflammation in metabolic disease. Within this project, we investigated the potential interaction of these protein on the molecular level, in cell experiments, and in animal models. Our experiments revealed that ZAG affects the release of fatty acids from adipocytes independent of SSAO, while SSAO has no effect on lipolysis. In contrast to published data, however, we did not observe a stimulation of fatty acid release, but inhibition of hormone-stimulated lipolysis by ZAG. In animal experiments, we could observe moderate effects on obesity in mice lacking ZAG, but not in SSAO-deficient mice. Tumor-induced cachexia was unchanged in both animal models. Our results suggest that ZAG affects the hormone-sensitivity of adipocytes independent of SSAO. However, neither ZAG nor SSAO appear to play a major role in the pathogenesis of timor-induced cachexia.