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.

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The objective was to determine the degree of correspondence in plasma cholesterol concentration changes caused by dietary cholesterol (DC) versus plant sterols (PS) and their effects on cholesterol trafficking. A randomized, cross‐over, placebo controlled free‐living clinical trial (n=51) with 3 treatment phases of 4 week duration each separated by a 4 week washout was conducted. During each phase, participants consumed one of the three treatments containing 0.6 g DC, 2 g PS/day or a placebo after breakfast meal. Plasma lipid profile was determined and cholesterol absorption (CA) was measured by using a stable isotope [3, 4‐13C]‐labeled cholesterol administered orally. Cholesterol synthesis (CS) was assessed using plasma lathosterol as a surrogate marker. DC intake increased total cholesterol (TC) compared to placebo (0.16 mmol/L; P = 0.037) and PS (0.25 mmol/L; P = 0.005). PS intake reduced (0.20 mmol/L; P = 0.042) LDL‐C only compared to DC. Cholesterol absorption was inhibited (P = 0.0001) by PS consumption compared to placebo. Results showed that the degree of cholesterol lowering with PS intake was not in concordance with the cholesterol elevating offset caused by DC intake with respect to TC and LDL‐C. The offsets in CA and CS caused by DC and PS did not align with those of LDL‐C and TC. The large inter‐individual variability in the plasma lipid responsiveness to PS and DC intake in the population could be ascribed to the above results.

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