Factors affecting circulating phytosterol levels: Toward an integrated understanding of atherogenicity and atheroprotection by dietary and circulating phytosterols

The amount of dietary phytosterols is comparable to that of cholesterol. The ABCG5/G8 transporters eliminate phytosterols in the gut, maintaining their circulating levels at less than 1% of cholesterol. Dysfunction of ABCG5/G8 leads to sitosterolemia (also known as ‘phytosterolemia’). Elevated phytosterols replace membrane cholesterol, causing hematologic cell lysis and organ failure. In sitosterolemia, premature atherosclerosis is often observed, linking elevated circulating phytosterols to their possible atherogenicity. However, human and animal studies do not seem to support elevated phytosterols as a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). In this review, we conducted a meta-analysis of circulating cholesterol and phytosterol levels prior to medical interventions in individuals with sitosterolemia. The analysis revealed that severe hypercholesterolemia manifests in the first decade of life but declines rapidly into adulthood, suggesting the presence of hypercholesterolemia-induced ASCVD in the patients. We also provide a comparison of circulating phytosterol levels in non-sitosterolemic subjects and animal models while providing a comprehensive analysis of factors influencing circulating phytosterol levels. Genetics and metabolic disturbances alter these levels, potentially confounding the relationship between phytosterol levels and ASCVD risk. The consumption of phytosterol-fortified foods does not significantly impact phytosterol levels in the body in the normal population, but it lowers circulating cholesterol levels by about 10%. Thus, assessing the association between phytosterols and ASCVD risk requires careful consideration of both cholesterol and phytosterol levels, along with the impact of confounding factors, to ensure accurate risk evaluation.