ROLE OF THE PRENYLCYSTEINE OXIDASE 1 IN THE REGULATION OF CARDIOMETABOLIC RISK FACTORS

Cardiometabolic syndrome (CMS) is a metabolic dysfunction caused by a combination of insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension and adiposity, influenced by obesity rates and sedentary lifestyles. CMS is influenced by a complex interplay of metabolic dysregulation, cardiovascular diseases (CVDs), and type 2 diabetes (T2D) risk factors, along with ageing, gender and family history. Research has continued to provide new insights into the pathophysiology of CMS leading to atherosclerosis and the mechanisms of its clinical complications. The accumulation of adipose tissue, in particular of visceral white adipose tissue (WAT) is the centrepiece of CMS and triggers metabolic interference and modifications that contribute to the progression of CMS complexity. Using a proteomic approach we found, in human lipoproteins, the presence of prenylcysteine oxidase (PCYOX1), a protein whose biological functions, since its discovery in 1997, have been exclusively restricted to the metabolism of prenylated proteins. We also provided evidence that PCYOX1, in the human atherosclerotic lesions, is both synthetized locally and transported within the subintimal space by proatherogenic lipoproteins accumulating in the arterial wall during atherogenesis. Further, PCYOX1 deficiency in ApoE-/- mice retards atheroprogression, improves plasma lipid profile, and reduces body weight, WAT deposition, glycemia and inflammation. These findings identify PCYOX1 as a novel player in atherogenesis. Assumed the role that PCYOX1 plays in atherosclerosis progression and lipid dysregulation, we decided to investigate if it could have also a role in the regulation of CMS, studying its effects on CMS main risk factors. PCYOX1 is critically involved in adipogenic differentiation and lipid regulation, modulating the early and the late factors involved in adipogenesis both in vitro and ex vivo. PCYOX1 deletion is also associated with reduced inflammation in the WAT of ApoE-/- PCYOX deficient animals fed with high fat diet. Moreover, also cardiac function results to be preserved in a C57BL/6J PCYOX1 knockout model. Further studies will be focused on the validation of PCYOX1 as candidate marker of CMS progression and on the evaluation of its effects in all the mechanisms known to be involved in CMS development.