# Factors Affecting Circulating Phytosterol Levels: Toward an Integrated Understanding of Atherogenicity and Atheroprotection by Dietary and Circulating Phytosterols

## TL;DR

This paper reviews how phytosterols can both protect against and contribute to heart disease, aiming to clarify their role in health.

## Contribution

The paper provides a quantitative meta-analysis and reframes the debate on phytosterol atherogenicity using empirical data.

## Key findings

- Severe hypercholesterolemia in sitosterolemia declines rapidly into adulthood.
- Phytosterol consumption lowers cholesterol by about 10% in the general population.
- Mendelian randomization links phytosterol levels to ASCVD risk, but genetic and metabolic factors complicate interpretation.

## Abstract

Dysfunction of the ATP-binding cassette G5/G8 heterodimier (ABCG5/G8) leads to sitosterolemia, a condition in which premature atherosclerosis is often observed, thereby linking elevated circulating phytosterols to atherogenicity. Conversely, consumption of phytosterols reduces circulating cholesterol levels and, in animal studies, is anti-atherogenic. The debate over phytosterols’ benefits vs. harms continues without consensus. Two key issues remain: despite extensive research, the etiology of premature atherosclerosis in sitosterolemia is still uncertain, and discussion of phytosterol atherogenicity has not been grounded in quantitative evidence, hindering true risk assessment.

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 atherosclerotic cardiovascular disease (ASCVD). Although ABCG5/G8-deficient animal models recapitulate the symptoms of sitosterolemia, including hematologic abnormalities and organ dysfunction, increased atherogenicity has not been observed in these models. By contrast, the consumption of phytosterol-supplemented foods minimally influences circulating phytosterol levels in the general population and lowers circulating cholesterol levels by approximately 10%. Mendelian randomization studies have indicated an association between circulating phytosterol levels and ASCVD risk; however, genetic background, sterol absorption efficiency, and metabolic disturbances modulate these levels, potentially confounding the interpretation of such associations.

This review reframes the phytosterol atherogenicity debate through quantitative assessment and clarifies longstanding uncertainties about phytosterol safety, thus contributing to evidence-based risk evaluation and supporting informed clinical and dietary recommendations.

The online version contains supplementary material available at 10.1007/s11883-025-01334-7.