Mevalonic Acid in Human Plasma: Relationship of Concentration and Circadian Rhythm to Cholesterol Synthesis Rates in Man

We tested the hypothesis that the rate of cholesterol synthesis in tissues determines the concentrations of mevalonic 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 of plasma 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 of MVA, an obligate precursor of cholesterol, in amounts apparently related to the rate of cholesterol synthesis offers a noninvasive, non-isotopic method for studying cholesterol synthesis in man.