The interplay between non-esterified fatty acids and plasma zinc and its influence on thrombotic risk in obesity and type 2 diabetes

Thrombosis is a major comorbidity of obesity and type-2 diabetes mellitus (T2DM). Despite the development of numerous effective treatments and preventative strategies to address thrombotic disease in such individuals, the incidence of thrombotic complications remains high. This suggests that not all the pathophysiological mechanisms underlying these events have been identified or targeted. Non-esterified fatty acids (NEFAs) are increasingly regarded as a nexus between obesity, insulin resistance and vascular disease. Notably, plasma NEFA levels are consistently elevated in obesity and T2DM and may impact haemostasis in several ways. A potentially unrecognised route of NEFA-mediated thrombotic activity is their ability to disturb Zn²⁺ speciation in the plasma. Zn²⁺ is a potent regulator of coagulation and its availability in the plasma is monitored carefully through buffering by human serum albumin (HSA). The binding of long-chain NEFAs such as palmitate and stearate however trigger a conformational change in HSA that reduce its ability to bind Zn²⁺ thus increasing the ion’s availability to bind and activate coagulation proteins. NE-FA-mediated perturbation of HSA-Zn²⁺ binding is thus predicted to contribute to the prothrom-botic milieu in obesity and T2DM, representing a novel targetable disease mechanism in these disorders.