Mevalonic acid in human plasma: relationship of concentration and circadian rhythm to cholesterol synthesis rates in man.

Abstract

We tested the hypothesis that the rate of cholesterol synthesis in tissues determines the concentrations of mevaIonic acid (MVA) in plasma. We found that plasma MVA concentrations were correlated (i) with increased rates of whole-body cholesterol synthesis (measured by sterol-balance methods) in patients treated with cholestyramine resin and (ii) with decreased rates of whole-body sterol synthesis (indicated by conversion of labeled acetate to sterol in freshly isolated mononuclear leukocytes) in out-patients after 4 weeks on a cholesterol-rich diet. In addition, a diurnal rhythm of plasma MVA concentrations was observed in patients whose activities were strictly controlled on a metabolic ward. At the peak of the rhythm (between midnight and 3 a.m.) MVA concentrations were 3-5 times greater than at the nadir (between 9 a.m. and noon). Furthermore, a relationship between the diurnal rhythm ofplasma MVA and endogenous cholesterol synthesis is suggested by our finding that the plasma MVA rhythm was suppressed by cholesterol feeding (1,200 mg/day) and abolished by a 12-day fast. The presence in human plasma ofMVA, an obligate precursor of cholesterol, in amounts apparently related to the rate ofcholesterol synthesis offers a noninvasive, nonisotopic method for studying cholesterol synthesis in man.Human cholesterol metabolism, as revealed by the sterol-balance method or by analysis ofcholesterol kinetics, is controlled by a system of homeostatic mechanisms that resists expansion or depletion of body cholesterol pools (1-3). The recent demonstration of rapid short-term regulation of the rate-limiting enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA reductase (NADPH) (E.C. 1.1.1.34), in animals by regulation of enzyme synthesis (4) and by a phosphorylation cascade (5) has created a need for new methods capable ofmeasuring rapid changes in the rate ofcholesterol synthesis in man. Existing methods are either invalid in the metabolic unsteady state (e.g., sterol balance or analysis of cholesterol kinetics) or they respond only to long-standing changes [e.g., squalene kinetics (6) and sterol synthesis in freshly isolated mononuclear leukocytes (7)].In this report we confirm the observations ofHagenfeldt and Hellstrom (8) and of Popjak et aL (9) that mevalonic acid (MVA) can be detected in human plasma. Furthermore, we demonstrate that the concentration of MVA is related to the rate of whole-body cholesterol synthesis. In addition, our studies show the existence of a diurnal rhythm of plasma MVA that is abolished by fasting and is reduced in amplitude by cholesterol feeding. Sources of variation in the relationship between wholebody cholesterol synthesis and plasma MVA concentration are considered in order to evaluate the usefulness of measuring plasma MVA levels as a sensitive and noninvasive method for estimating cholesterol synthesis rates in human subjects without the need for in vivo administration of radioactive materials. MATERIALS AND METHODSOut-Patient Volunteers and Their Diets. Ten male p...

Morphologic and Biochemical Changes in Dogs After Portacaval Shunt Plus Bile Fistula or Ileal Bypass: Failure of Bile Fistula or Ileal Bypass to Prevent Hepatocyte Atrophy

“…(19), as modified by Parker et a1. (20). Attempts to analyse postprandial samples for mevalonic acid proved to be impractical because of the presence in the plasma of substances that interfered with the measurement.…”

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Rosuvastatin Using an Extension of the Indirect Response Model by Incorporating a Circadian Rhythm

“…5) Despite the importance of HMG-CoA reductase inhibitors in the management of dyslipidemia, the relationship between drug exposure and the extent of HMG-CoA inhibition has not been elucidated. In general, peak cholesterol biosynthesis occurs at night, 6) suggesting that the hypocholesterolemic effects of HMG-CoA reductase inhibitors are stronger after evening administration than after morning administration. However, robust trials are necessary to determine the best administration time to achieve optimal LDL-C lowering for rosuvastatin.…”

Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion

“…Studies in our laboratory and others have shown that changes in the concentrations of mevalonate in plasma and urine reflect parallel changes in the activity of hepatic HMG-CoA reductase and thus normally reflect changes in the rates of whole body cholesterol biosynthesis (22)(23)(24)(25). While plasma concentrations of mevalonic acid exhibit diurnal variations with peak values occurring at night (25)(26)(27), the mean 24-h plasma concentration is an accurate indicator of the rates of hepatic (whole body) cholesterol synthesis under different metabolic conditions. The 24-h urinary excretion of mevalonate reflects the integrated plasma concentration and provides a more practical and non-invasive way of assessing whole body cholesterol synthesis.…”