Studies were carried out to examine the effects of dietary fat and cholesterol on cholesterol homeostasis in man. 75 12-wk studies were carried out during intake of 35% of calories as either saturated or polyunsaturated fat, first low and then high in dietary cholesterol. Dietary fat and cholesterol intakes, plasma lipid and lipoprotein levels, cholesterol absorption and sterol synthesis in isolated blood mononuclear leukocytes were measured during each diet period. In 69% of the studies the subjects compensated for the increased cholesterol intake by decreasing cholesterol fractional absorption and/or endogenous cholesterol synthesis. When an increase in plasma cholesterol levels was observed there was a failure to suppress endogenous cholesterol synthesis. Plasma cholesterol levels were more sensitive to dietary fat quality than to cholesterol quantity.The results demonstrate that the responses to dietary cholesterol and fat are highly individualized and that most individuals have effective feedback control mechanisms.

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...

A s bstract. Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p < 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol.The hypothesis that short-term regulation of HMGCoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dosedependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant

Measurements of the key parameters of cholesterol homeostasis and the mass of the body pools of cholesterol were carried out in two patients with familial hypercholesterolemia (FH), one homozygote and one heterozygote, before and 28 and 18 months, respectively, after portacaval anastomosis (PCA). In both patients the procedure significantly reduced the plasma concentrations of total and low density lipoprotein cholesterol and the daily rate of whole body cholesterol and bile acid synthesis. In addition, PCA caused a net efflux of accumulated tissue cholesterol as demonstrated by reductions in the rapidly exchangeable and total exchangeable masses of body cholesterol. Shunt patency was verified by demonstration of increased bile acids in serum from fasting patients and from patients 2 hr after a meal and by increased plasma glucagon before and after arginine infusion. Other than a persistently increased level of serum alkaline phosphatase, liver function tests have fallen within the normal range in both patients; there has been no evidence of hepatic encephalopathy. In the homozygous patient there has also been a striking resolution in xanthoma size and distribution. These multiple effects on cholesterol homeostasis and pool sizes strongly suggest that PCA can reverse the progressive accumulation of cholesterol in body tissues of FH patients.Familial hypercholesterolemia (FH) is an autosomal dominant genetic defect resulting in decreased numbers ofcell receptors for low density lipoprotein (LDL) (1). This inborn error of metabolism is characterized by increased plasma LDL, deposition of cholesterol in subcutaneous and tendinous tissues (xanthomata), and premature cardiovascular disease (2). Analysis of plasma cholesterol decay kinetics has shown that FH patients have significantly increased body cholesterol pools (3, 4) in addition to an overproduction of LDL (5,6). Metabolic studies have demonstrated that young homozygous FH (HmFH) patients have an increased rate of cholesterol synthesis that decreases to normal rates with increasing age (7,8).Portacaval anastomosis (PCA) has been shown to cause marked reductions in plasma cholesterol concentrations in HmFH patients. This intervention, introduced in FH by Starzl et al. in 1973 (9), has been used as a treatment modality in more than 30 HmFH patients (10-14); postoperatively, most patients have experienced a striking resolution ofxanthomata along with decreases in synthesis rates of LDL and cholesterol (11).In a recent report from this laboratory (15) it was demonstrated in the rat that PCA significantly reduced plasma cholesterol and the rate ofwhole body cholesterol synthesis. It was shown also that PCA caused a decrease in net tissue cholesterol content as compared to untreated control animals. Because rats with shunts exhibited normal growth rates, it could not be determined whether the PCA caused a redistribution of body cholesterol pools or whether a net efflux of tissue cholesterol had occurred.To extend our previous studies of cholesterol homeost...

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