Quantitative relations between dietary fat and cholesterol and plasma lipid concentrations have been the subject of much study and some controversy during the past 40 y. Previous meta-analyses have focused on the most tightly controlled, highest-quality experiments. To test whether the findings of these investigations are generalizable to broader experimental settings and to the design of practical dietary education interventions, data from 224 published studies on 8143 subjects in 366 independent groups including 878 diet-blood lipid comparisons were subjected to weighted multiple-regression analysis. Inclusion criteria specified intervention studies published in English between 1966 and 1994 reporting quantitative data on changes in dietary cholesterol and fat and corresponding changes in serum cholesterol, triacylglycerol, and lipoprotein cholesterol concentrations. Regression models are reported for serum total cholesterol, triacylglycerol, and low-density-high-density-, and very-low-density-lipoprotein cholesterol, with multiple correlations of 0.74, 0.65, 0.41, 0.14, and 0.34, respectively. Interactions of dietary factors, initial dietary intakes and serum concentrations, and study and subject characteristics had little effect on these models. Predictions indicated that compliance with current dietary recommendations (30% of energy from fat, < 10% from saturated fat, and < 300 mg cholesterol/d) will reduce plasma total and low-density-lipoprotein-cholesterol concentrations by approximately 5% compared with amounts associated with the average American diet.

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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.

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

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...

For over 25 years eggs have been the icon for the fat, cholesterol and caloric excesses in the American diet, and the message to limit eggs to lower heart disease risk has been widely circulated. The "dietary cholesterol equals blood cholesterol" view is a standard of dietary recommendations, yet few consider whether the evidence justifies such restrictions. Over 50 years of cholesterol-feeding studies show that dietary cholesterol does have a small effect on plasma cholesterol concentrations. The 167 cholesterol feeding studies in over 3,500 subjects in the literature indicate that a 100 mg change in dietary cholesterol changes plasma total cholesterol by 2.2 mg/dL. Today we recognize that dietary effects on plasma cholesterol must be viewed from effects on the atherogenic LDL cholesterol as well as anti-atherogenic HDL cholesterol since the ratio of LDL:HDL cholesterol is a major determinant of heart disease risk. Cholesterol feeding studies demonstrate that dietary cholesterol increases both LDL and HDL cholesterol with little change in the LDL:HDL ratio. Addition of 100 mg cholesterol per day to the diet increases total cholesterol with a 1.9 mg/dL increase in LDL cholesterol and a 0.4 mg/dL increase in HDL cholesterol. On average, the LDL:HDL ratio change per 100 mg/day change in dietary cholesterol is from 2.60 to 2.61, which would be predicted to have little effect on heart disease risk. These data help explain the epidemiological studies showing that dietary cholesterol is not related to coronary heart disease incidence or mortality across or within populations.

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The 1968 American Heart Association announced a dietary recommendation that all individuals consume less than 300 mg of dietary cholesterol per day and no more than three whole eggs per week. This recommendation has not only significantly impacted the dietary patterns of the population, but also resulted in the public limiting a highly nutritious and affordable source of high quality nutrients, including choline which was limited in the diets of most individuals. The egg industry addressed the egg issue with research documenting the minimal effect of egg intake on plasma lipoprotein levels, as well as research verifying the importance of egg nutrients in a variety of issues related to health promotion. In 2015 dietary cholesterol and egg restrictions have been dropped by most health promotion agencies worldwide and recommended to be dropped from the 2015 Dietary Guidelines for Americans.