Not all the eggs and the chickens are the same: The case of uric acid and metabolic syndrome

Uric acid represents the end-product of purine metabolism in humans and the great apes where it has played some evolutive roles over the time [ [1] Bardin T. Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014; 26: 186-191 Crossref PubMed Scopus (218) Google Scholar ]. The production of uric acid is largely regulated by xanthine oxidoreductase (XOR) that is converting hypoxanthine to uric acid and is partially responsible for the increase in the serum levels of urate and its possible biological and pathological effects [ [1] Bardin T. Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014; 26: 186-191 Crossref PubMed Scopus (218) Google Scholar ]. Historically the increase in serum urate has been linked to some dietary habits (e.g. alcohol, red meat, seafood, etc.) that however explain only a minor proportion of the variance in serum uric acid levels when compared with inherited genetic variants [ [2] Choi H._.K. Atkinson K. Karlson E.W. Willett W. Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004; 350: 1093-1103 Crossref PubMed Scopus (761) Google Scholar ]. More importantly, uric acid is also synthesized in the liver, intestines, muscle, and vascular endothelium and this endogenous production could be more strictly related to the effects of increased serum urate beyond its crystal precipitation at the level of joints, soft tissue, kidneys, and other organs [ [3] El Ridi R. Tallima H. Physiological functions and pathogenic potential of uric acid: a review. J Adv Res. 2017; 8: 487-493 Crossref PubMed Scopus (167) Google Scholar ]. Accumulating evidence has demonstrated the role of increased serum urate as a possible etiologic mechanism in the pathogenesis of cardiovascular, metabolic, and renal diseases [ 4 Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar , 5 Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar , 6 Borghi C. Agnoletti D. Cicero A.F.G. Lurbe E. Virdis A. Uric acid and hypertension: a review of evidence and future perspectives for the management of cardiovascular risk. Hypertension. 2022 Jun 6; (101161HYPERTENSIONAHA12217956) Crossref PubMed Google Scholar ]. In particular, the presence of hyperuricemia above the levels of 5.5 mg/dL has been reported as a risk factors for hypertension, atrial fibrillation (AF), chronic kidney disease (CKD), heart failure (HF), coronary artery disease (CAD), and cardiovascular death [ [4] Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar , [5] Borghi C. Agabiti-Rosei E. Johnson R.J. Kielstein J.T. Lurbe E. Mancia G. Redon J. Stack A.G. Tsioufis K.P. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020; 80: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar ]. In addition, elevated levels of serum uric acid have been reported to increase the relative risk of diabetes and metabolic syndrome acting though an interference with insulin sensitivity that has been reported as significantly reduced in presence of increased serum urate before the development of hyperglycemia and correlated risk factors [ [7] Han T. Lan L. Qu R. Xu Q. Jiang R. Na L. Sun C Temporal relationship between hyperuricemia and insulin resistance and its impact on future risk of hypertension. Hypertension. 2017; 70 (Oct): 703-711 Crossref PubMed Scopus (43) Google Scholar ]. This observations and many others in the same direction have supported the idea that uric acid per se or the mechanism of its production can be involved in the progressive reduction in tissue insulin sensitivity that may explain the progression toward metabolic abnormalities, increased blood pressure and atherogenic dyslipidemia that can largely contribute to the excess in the risk of cardiovascular disease observed in patients with elevated serum urate levels.