Revisiting Human Cholesterol Synthesis and Absorption: The Reciprocity Paradigm and its Key Regulators

Abstract Hypercholesterolemia is a major risk factor for cardiovascular disease. Cholesterol homeostasis in the body is governed by the interplay between absorption, synthesis, and excretion or conversion of cholesterol into bile acids. A reciprocal relationship between cholesterol synthesis and absorption is known to regulate circulating cholesterol in response to dietary or therapeutic interventions. However, the degree to which these factors affect synthesis and absorption and the extent to which one vector shifts in response to the other are not thoroughly understood. Also, huge inter‐individual variability exists in the manner in which the two systems act in response to any cholesterol‐lowering treatment. Various factors are known to account for this variability and in light of recent experimental advances new players such as gene–gene interactions, gene–environmental effects, and gut microbiome hold immense potential in offering an explanation to the complex traits of inter‐individual variability in human cholesterol metabolism. In this context, the objective of the present review is to provide an overview on cholesterol metabolism and discuss the role of potential factors such as genetics, epigenetics, epistasis, and gut microbiome, as well as other regulators in modulating cholesterol metabolism, especially emphasizing the reciprocal relationship between cholesterol synthesis and absorption. Furthermore, an evaluation of the implications of this push–pull mechanism on cholesterol‐lowering strategies is presented.