Strategies for Therapeutic Amelioration of Aberrant Plasma Zn2+ Handling in Thrombotic Disease: Targeting Fatty Acid/Serum Albumin-Mediated Effects

Abstract

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn2+ in blood plasma. Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70–85% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.

Zinc in Prostate Health and Disease: A Mini Review

“…Various binding affinities of these metal ions are also described [ 29 ], indicating competition for Zn 2+ binding at these sites. Zn binding to albumin also competes with free fatty acids [ 32 ], and free fatty acid binding changes the structure of serum albumin and reduces its affinity for Zn 2+ [ 33 ]. Meanwhile, prostate cancer patients report higher levels of free fatty acids in the serum compared to men without prostate cancer, and in vitro studies with PC3 (cell line derived from human prostate cancer bone metastasis) and 22RV1 (prostate carcinoma epithelial cell line derived from a xenograft) cells have shown that free fatty acids promote the proliferation, migration, and invasion of these cells [ 34 ].…”

“…Until such time it is important to understand how to optimize the use of ingested Zn with lifestyle modifications and good health. These include cessation of tobacco smoking habits that cause higher systemic Cd burden [ 169 , 186 ] and compete with Zn binding sites on albumin and MTs; changing excessive alcohol consumption lifestyle known to associate with higher blood Cd levels [ 169 ]; refraining from excessive intakes of high-fat diets to prevent competition on Zn circulation through albumin [ 32 ] and preserve albumin structure for proper function [ 33 ]; minimizing stress to reduce ROS to facilitate stability of ZF proteins [ 124 ]; increasing consumption of fermented or germinated food products to avoid phytates to support Zn binding to albumin for circulation [ 20 ]; manage blood sugar levels to minimize diabetes or pre-diabetes which are known to associate with Zn urinary excretion [ 187 ]; increased plant-based diets to improve Zn transporter regulation by the phytochemical action [ 159 ], and plant fiber to increase gut transit time to optimize Zn absorption.…”

Stability and Thrombogenicity Analysis of Collagen/Carbon Nanotube Nanocomposite Coatings Using a Reversible Microfluidic Device

“…It is known that excessive appearance of blood albumin protein molecules adhered to the surface of vessels or implanted products is a precursor of thrombosis [50][51][52][53]. Therefore, the evaluation of BSA protein adhesion to the nanocomposite coating was used to determine the degree of thrombogenicity.…”