Can PM20D1 be a New Kid on the Block in Cardiovascular Risk Stratification? Do Not Run before You Can Walk

Cardiovascular diseases are the leading cause of death worldwide, representing around 30% of all deaths, particularly in developed countries, including cardiovascular and cerebral-vascular diseases. Furthermore, in the analysis of the Global Burden of Diseases 2019 report, cardiovascular risk factors represent 75% of all cardiovascular burden, particularly hypertension, with an important impact on mortality. This is also relevant in Portuguese-speaking countries. Carotid intima-media thickness has long been recognized as a surrogate marker for coronary artery disease and has a relevant prognostic impact. For that reason, it is a useful tool in cardiovascular risk stratification.

N-acyl amino acids (NAAA) are a family of cold-inducible circulating lipids that stimulate thermogenesis, and their biosynthesis in brown adipocytes is mediated by a secreted enzyme called Peptidase M20 domain containing 1 (PM20D1). PM20D1 and NAAA activity regulation in blood plasma is still largely unknown. However, what is already known is that PM20D1 circulates in tight association with both low- and high-density lipoproteins that are powerful co-activators of PM20D1 activity in vitro and NAAA biosynthesis in vivo. Serum albumin is also a physiologic NAAA carrier that separates NAAA away from their sites of production, conferring resistance to hydrolytic degradation and establishing an equilibrium between thermogenic “free” versus inactive “bound” fractions. It has been hypothesized that lipoprotein particles are probably the main extracellular sites of NAAA biosynthesis, and this supports the concept that a lipoprotein-albumin network regulates the activity of circulating thermogenic lipid family.

[…]