Uric acid inhibition of dipeptidyl peptidase IV in vitro is dependent on the intracellular formation of triuret

Abstract

Uric acid affects endothelial and adipose cell function and has been linked to diseases such as hypertension, metabolic syndrome, and cardiovascular disease. Interestingly uric acid has been shown to increase endothelial progenitor cell (EPC) mobilization, a potential mechanism to repair endothelial injury. Since EPC mobilization is dependent on activity of the enzyme CD26/dipeptidyl peptidase (DPP)IV, we examined the effect uric acid has on CD26/DPPIV activity. Uric acid inhibited the CD26/DPPIV associated with human umbilical vein endothelial cells but not human recombinant (hr)CD26/DPPIV. However, triuret, a product of uric acid and peroxynitrite, could inhibit cell associated and hrCD26/DPPIV. Increasing or decreasing intracellular peroxynitrite levels enhanced or decreased the ability of uric acid to inhibit cell associated CD26/DPPIV respectively. Last, protein modeling demonstrates how triuret can act as a small molecule inhibitor of CD26/DPPIV activity. This is the first time that uric acid or a uric acid reaction product has been shown to affect enzymatic activity and suggests a novel avenue of research in the role of uric acid in the development of clinically important diseases.

Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats

“…Previous reports demonstrate a critical role for oxidants in stimulating NFAT5 transcriptional activity (31,32). In this regard, uric acid, despite being an important antioxidant in the systemic circulation, can also act as a prooxidant molecule intracellularly (9,33). Consistently, and as shown in Fig.…”

DPP4 Polymorphisms Are Associated With Hypoalphalipoproteine mia and DPP4 Serum Levels. A Case-control Study of the GEA Cohort.

“…However, it is well recognized that hyperuricemia is associated with metabolic diseases and endothelial dysfunction. Consistent with our observed association between variation in DPP4 polymorphisms and hyperuricemia, Mohandas et al demonstrated that uric acid inhibits DPP4 activity when it is anchored to the membrane and that the inhibitory effect depends on the redox state of cells and formation of intracellular triuret [58].…”

The rs12617336 and rs17574 Dipeptidyl Peptidase-4 Polymorphisms Are Associated With Hypoalphalipoproteinemia and Dipeptidyl Peptidase-4 Serum Levels: A Case-Control Study of the Genetics of Atherosclerotic Disease (GEA) Cohort

“…We reported an association of the rs12617336 minor allele with a high risk of hyperuricemia. The relationship between the uric acid and DPP4 was established by Mohandas et al, who demonstrated that uric acid inhibits DPP4 activity when it is anchored to the membrane and that the inhibitory effect depends on the redox state of cells and the formation of intracellular triuret (Mohandas et al, 2014).…”