Non-Cholesterol Sterol Concentrations As Biomarkers For Cholesterol Absorption And Synthesis In Different Metabolic Disorders: A Systematic Review

Abstract

Non-cholesterol sterols are validated biomarkers for intestinal cholesterol absorption and endogenous cholesterol synthesis. However, their use in metabolic disturbances has not been systematically explored. Therefore, we conducted a systematic review to provide an overview of non-cholesterol sterols as markers for cholesterol metabolism in different metabolic disorders. Potentially relevant studies were retrieved by a systematic search of three databases in July 2018 and ninety-four human studies were included. Cholesterol-standardized levels of campesterol, sitosterol and cholestanol were collected to reflect cholesterol absorption and those of lathosterol and desmosterol to reflect cholesterol synthesis. Their use as biomarkers was examined in the following metabolic disorders: overweight/obesity (n = 16), diabetes mellitus (n = 15), metabolic syndrome (n = 5), hyperlipidemia (n = 11), cardiovascular disease (n = 17), and diseases related to intestine (n = 16), liver (n = 22) or kidney (n = 2). In general, markers for cholesterol absorption and synthesis displayed reciprocal patterns, showing that cholesterol metabolism is tightly regulated by the interplay of intestinal absorption and endogenous synthesis. Distinctive patterns for cholesterol absorption or cholesterol synthesis could be identified, suggesting that metabolic disorders can be classified as 'cholesterol absorbers or cholesterol synthesizers'. Future studies should be performed to confirm or refute these findings and to examine whether this information can be used for targeted (dietary) interventions.Nutrients 2019, 11, 124 2 of 31 procedures [5]. The only direct method to measure intestinal cholesterol absorption in humans is the intestinal perfusion technique using radioisotopes [6], whereas cholesterol balance and isotope ratio methods can be used to indirectly calculate cholesterol absorption. Cholesterol absorption using stable isotopes can be estimated using the dual plasma isotope ratio method, continuous isotope feeding, or single stable isotopes [5]. For quantifying endogenous cholesterol synthesis, other techniques such as cholesterol balance, fractional conversion of squalene, mass isotopomer distribution analysis (MIDA), and deuterium incorporation (DI) are used. Overall, the cholesterol balance technique, dual plasma isotope ratio, and continuous isotope feeding are the gold standard methods to quantify respectively cholesterol synthesis and absorption. These methods were developed and validated many years ago [7][8][9][10]. However, although these techniques are very precise, they are also complex, laborious, expensive and require a steady-state condition. Thus, these techniques are only suitable for small-scale in-depth studies, but not for large-scale intervention studies [11]. Consequently, there is a clear need for alternative approaches to monitor intestinal cholesterol absorption and endogenous cholesterol synthesis. In the early 90s, serum non-cholesterol sterols were introduced as validated biomarkers for assessing intestina...

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Lathosterol in plasma measures cholesterol synthesis and identifies the efficiency of dietary phytosterols in reducing the plasma cholesterol concentration

“…Our data contribute to explain investigation in cases of metabolic syndrome in which decreased intestinal absorption of cholesterol is associated with lower efficiency of PS esters in reducing blood cholesterol although the cholesterol synthesis markers had not been measured [31]. Such a result may be consequent to elevated cholesterol synthesis in cases of metabolic syndrome [16]. In summary, responders absorbed more PS than non-responders likely resulting from responders delivering less endogenous cholesterol into the intestinal lumen that facilitates greater absorption of PS by the intestine.…”

“…Plasma concentrations of PS, and of non-cholesterol sterol precursors of cholesterol synthesis, respectively, markers of the intestinal cholesterol absorption and of the body's cholesterol synthesis have been utilized as markers of atherosclerotic cardiovascular disease [12] [13] [14] [15] [16] [17].…”

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“…An important limitation of the present study is the use of serum markers of cholesterol synthesis and absorption rather than isotope tracer measurements which directly assess cholesterol synthesis and absorption 32‐34 . However, such direct measurements are not practical in a cohort of this size and serum markers of synthesis and absorption correlate well with direct measurements 35‐39 …”