Circulatory zinc dyshomeostasis as a novel contributor of thrombosis in obesity and Type II diabetes mellitus

Abstract

Individuals with obesity and Type II diabetes mellitus are particularly susceptible to pathological thrombosis. Notably, the formation of highly compact clots which are resistant to breakdown is likely to contribute to thrombotic risk in these disease groups. High thrombotic risk in these diseases may also be driven by altered Zn²⁺ dynamics in the plasma. Zn²⁺ is a key modulator of haemostasis and influences the activities of numerous coagulation proteins. Normally, Zn²⁺ ions are buffered by human serum albumin (HSA). However, increased levels of non-esterified fatty acids (NEFAs) in obesity and type II diabetes disrupt Zn²⁺ binding to HSA. This may lead to clotting issues, where other Zn²⁺ binding proteins, such as histidine rich glycoprotein (HRG), becomes recipients for these excess Zn²⁺ ions. The interaction between HRG and Zn²⁺ alters the behaviour of proteins involved in clotting, potentially contributing to the abnormal clot structures seen in these patients. This study explores the Zn²⁺-binding properties of HSA in the presence of NEFAs and identifies the second fatty acid binding site (FA2) as the specific site responsible for disrupting Zn²⁺ binding. The investigation also explores the structural and functional aspects of HRG in the presence of Zn²⁺ using various techniques. The findings of this study suggest that Zn²⁺ influences HRG's dynamics and oligomerization. The study has also explored the fibrin clot properties in obese individuals before and after bariatric surgery, correlating changes in fibrin clot properties with clinical parameters. Correlations were found between fibrin clot density and other clinical markers such as % HbA1c, triglycerides, C-reactive protein, and fibrinogen concentrations. Overall, this research underscores how altered Zn²⁺ dynamics in obesity and Type II diabetes can affect blood clotting, offering insights into potential mechanisms leading to abnormal clot structures in obesity and type II diabetes.