Probing the Biology of Zinc Alpha 2-Glycoprotein and the role it plays in cachexia

Abstract

Abstract Background Cachexia is a metabolic disease characterized by significant weight loss and muscle wasting, and it is responsible for a substantial number of cancer-related deaths. Zinc-alpha-2-glycoprotein (ZAG) plays a role in the regulation of weight and body fat through the metabolism of lipids and glucose. In healthy individuals, ZAG promotes homeostasis by inducing the breakdown of adipose tissue, leading to reduced fat storage and overall weight. However, in various carcinomas and cancer patients, upregulation of ZAG is observed, resulting in rapid weight loss. Mutations in ZAG, specifically the amino acids Tryptophan 148, Arginine 73, Phenylalanine 101, and Isoleucine 76, have been identified and replaced with Alanine. The effects of these mutants, as well as the wild-type ZAG, can be investigated through experimental studies. Additionally, ZAG is believed to have a lipid binding site that may be crucial for its function. Methods To assess the impact of ZAG variants on lipolysis, a lipolysis colorimetric kit was used to measure their effects on 3T3 adipose cells. This allowed for the determination of the β-adrenoreceptor signalling pathways involved in the lipolytic effect of ZAG. The lipolysis experiments were conducted over a specific time period, as the duration of treatment can be a limiting factor influencing lipolysis. Results Among the ZAG variants tested, the Tryptophan-Alanine mutant exhibited increased lipolysis after 1 hour of treatment compared to other variants. These findings suggest that the specific mutations in ZAG can influence its lipolytic activity. Conclusion Identifying the ligand(s) and understanding the interactions between them and ZAG is crucial in advancing our knowledge of the mechanisms underlying ZAG's function. Ultimately, the development of therapeutics targeting ZAG could provide cancer patients with treatment options to attenuate weight loss, leading to improved prognoses and a better quality of life.