Abstract
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 hemostasis in several ways. A potentially unrecognized 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 reduces its ability to bind Zn2+, thus increasing the ion’s availability to bind and activate coagulation proteins. NEFA-mediated perturbation of HSA-Zn2+ binding is thus predicted to contribute to the prothrombotic milieu in obesity and T2DM, representing a novel targetable disease mechanism in these disorders.
Highlights
Addition of up to 5 mol. eq of octanoate had little effect on Zn2+ binding to human serum albumin (HSA), but a change was seen with laurate and longer-chain saturated Non-esterified fatty acids (NEFAs), where the results suggested a reduction in the stoichiometry of site A with increasing NEFA
We recently addressed the question of whether NEFAs alter fibrin clot formation and lysis in a Zn2+ -dependent manner using turbidimetric studies that utilized either purified proteins or plasma, with clotting initiated by the addition of thrombin in both systems
Current evidence indicates that plasma NEFAs impact Zn2+ speciation via an allosteric mechanism on HSA in obese and type-2 diabetes mellitus (T2DM) disease states
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. There are several coagulation-related, Zn2+ -binding plasma proteins that may bind an increased proportion of Zn2+ when HSA-Zn2+ interactions are compromised by NEFA binding These include plasminogen, plasmin, tPA, fibrinogen, factor XIII, and histidinerich glycoprotein (HRG) [31,38,63,90]. Such evidence includes the observation that analbuminemia (HSA deficiency) is associated with hypercoagulability [101] While this is likely to be a result of a combination of factors, including altered concentrations of coagulation proteins, it is apparent that this would impact plasma Zn2+ availability (potentially increasing the proportion of Zn2+ able to bind coagulation proteins) and, Zn2+ -dependent hemostasis. We recently addressed the question of whether NEFAs alter fibrin clot formation and lysis in a Zn2+ -dependent manner using turbidimetric studies that utilized either purified proteins (fibrinogen and HSA) or plasma, with clotting initiated by the addition of thrombin in both systems. NEFAs induce changes in Zn2+ speciation [31], and that these changes drive prothrombotic events in obesity and T2DM [88]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
