The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

Abstract

The cholesterol balance procedure allows the calculation of cholesterol synthesis based on the assumption that loss of endogenous cholesterol via fecal excretion and bile acid synthesis is compensated by de novo synthesis. Under ezetimibe therapy hepatic cholesterol is diminished which can be compensated by hepatic de novo synthesis and hepatic extraction of plasma cholesterol. The plasma lathosterol concentration corrected for total cholesterol concentration (R_Lath) as a marker of de novo cholesterol synthesis is increased during ezetimibe treatment but unchanged under treatment with ezetimibe and simvastatin. Cholesterol balance derived synthesis data increase during both therapies. We hypothesize the following. (1) The cholesterol balance data must be applied to the hepatobiliary cholesterol pool. (2) The calculated cholesterol synthesis value is the sum of hepatic de novo synthesis and the net plasma—liver cholesterol exchange rate. (3) The reduced rate of biliary cholesterol absorption is the major trigger for the regulation of hepatic cholesterol metabolism under ezetimibe treatment. Supportive experimental and literature data are presented that describe changes of cholesterol fluxes under ezetimibe, statin, and combined treatments in omnivores and vegans, link plasma R_Lath to liver function, and define hepatic de novo synthesis as target for regulation of synthesis. An ezetimibe dependent direct hepatic drug effect cannot be excluded.

Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review

“…This study also demonstrated inverse correlations at baseline between cholesterol synthesis markers (ratios of plasma lathosterol-to-cholesterol and desmosterol-to-cholesterol) and cholesterol absorption markers (ratios of plasma sitosterol-to-cholesterol, campesterol-to-cholesterol and cholestanol-to-cholesterol). In a study by Stellaard et al [21], ezetimibe treatment of a population with normal daily cholesterol intake, serum ratios of sitosterol-to-cholesterol, campesterol-to-cholesterol and cholestanol-to-cholesterol were shown to reflect changes in fractional cholesterol absorption. In the same study, serum lathosterol-to-cholesterol ratios correlated with absolute cholesterol synthesis.…”

Simvastatin improves oral implant osseointegration via enhanced autophagy and osteogenesis of BMSCs and inhibited osteoclast activity

“…Simvastatin, known as a 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) reductase inhibitor, is widely used to decrease serum cholesterol because of its safe and effective treatment (Bjornsson, ; Stellaard & Lutjohann, ). Apart from cholesterol‐lowering effects, simvastatin is also found to promote osteogenic differentiation of BMSCs and suppress osteoclastic differentiation in bone tissue (Tai et al, ; Xu et al, ; Yue et al, ).…”

Cholesterol Absorption and Synthesis in Vegetarians and Omnivores

“…This was neither associated with higher values of plasma lathosterol or desmosterol concentrations nor with their marker:cholesterol ratios. Relating these markers to hepatic de novo synthesis, it could be speculated that the higher synthesis is due to intestinal synthesis compensating for the lower dietary intake. Interestingly, the fractional cholesterol absorption in vegans (mean 42%) was significantly lower than in omnivores (mean 50%).…”