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  • Measurement of Chol absorption synthesis and catabolism woul


    Measurement of Chol absorption, synthesis and catabolism would be very helpful to determine the underlying cause of hypercholesterolemia in individual patients at risk for atherosclerosis. The information could help to determine the best therapeutic approach to reduce Chol absorption, to reduce Chol synthesis, or to increase BAS. However, the complexity of the different experimental procedures prevents application as routine clinical diagnostic tests. Therefore, alternative procedures have been developed based on the measurement of surrogate markers in fasting serum that reflect FrChA, ChS and BAS. Plant sterols have been shown to use the same endothelial transport system for hygromycin b as cholesterol [19]. Reduction of FrChA results in a similar reduction in the fractional plant sterol absorption. For over 25 years, the fasting serum levels of campesterol (Camp) and sitosterol (Sit) corrected for the Chol levels (R_Camp and R_Sit) have been used to monitor the daily Chol absorption rate [20], [21], [22], [23], [24]. Also, serum cholestanol (Cholol), the 5α-saturated derivative of Chol, acts as a surrogate marker for FrChA [25]. Lathosterol (Lath) is the second last step of the Kandutsch-Russell part of the steroidal cholesterol synthesis pathway. Its serum concentration corrected for Chol concentration (R_Lath) has been identified as a valid surrogate marker to express the activity of ChS [26]. As surrogate markers for BAS, serum 7α-hydroxycholesterol or its follow-up product 7α-hydroxy-4-cholesten-3-one (C4) were established [27], [28], [29] and shown to correlate to BAS measurement performed with stable isotopes [30]. Bile acid synthesis is known to contain a neutral and major pathway based on cholesterol 7α-hydroxylation as the first and rate-limiting step as well as an acidic and minor pathway based on cholesterol 27-hydroxylation as the initial step. The validity of serum 7α-hydroxy-cholesterol (7α-OH-Ch) as surrogate marker for BAS was documented in a number of studies [28], [29]. Serum 27-hydroxy-cholesterol (27-OH-Ch) has not been investigated as a marker to date. Serum surrogate markers for Chol metabolism have been validated by comparison with established methods determining real functionality (absorption, synthesis, catabolism) or reflecting the expected change in function in patients during therapy. Possibly interfering dietary factors were studied and found to not disturb the validity of the markers [31]. Recently, Jakulj et al. published a comparison of serum plant sterol concentrations and FrChA determined by the blood based stable isotope approach [9], [32] and concluded that the serum plant sterol concentration does not reflect FrChA [33]. Interestingly, while surrogate marker technology has been applied in patients undergoing ezetimibe (EZE) treatment [34], [35], [36], [37], [38], application under EZE treatment has never been validated. The effect of EZE treatment alone or in combination with SIMVA treatment on FrChA and ChS has been studied applying the original function tests [39], [40]. In particular, the combined ezetemibe/statin treatment is a major challenge for surrogate markers when both Chol synthesis and absorption are downregulated. An intriguing aspect is the observation that EZE leads to increased ChS and increased total input calculated as ChS+DACh, however, eventually resulting in decreased serum total Chol and LDL-Chol concentrations [40]. Therefore, we decided to retrospectively investigate the validity of all of the different surrogate markers for FrChA, ChSand BAS in different combinations of EZE-induced reduced absorption and SIMVA-induced reduced synthesis. As a control situation, we also investigated FrChA and ChS and the corresponding markers in pure vegetarians (vegans), whose Chol intake is extremely low and whose FrChA was shown not to be impaired [41].
    Subjects and methods The data of 37 healthy omnivores and 18 vegans were retrospectively analyzed. The details of subject selection and the designs of the studies have been published previously and are summarized in Table 1 [40], [41]. Briefly, the omnivore study was a computer-randomized, double-blind, placebo-controlled, 4-period, balanced, crossover study comparing the effects of 10mg ezetimibe in combination with 20mg simvastatin (EZE+SIMVA), 10mg ezetimibe (EZE) alone, 20mg simvastatin (SIMVA) alone and placebo (PLAC) in the same subjects [40]. Each treatment period lasted seven weeks. In the vegetarian study, vegans were studied under PLAC and EZE treatment [41]. For this validation study, the PLAC data from the vegan subjects were compared to the PLAC data from the omnivore subjects. In the original omnivore study, only cholesterol absorption and cholesterol synthesis as well as BAS functions were measured. In the original vegetarian study, function and marker tests for Chol absorption and ChS were performed, but the values were not interrelated.