Hypo- and Hyperresponders: Individual Differences in the Response of Serum Cholesterol Concentration to Changes in Diet

Beynen, A.C.; Katan, Martijn B.; Zutphen, L.F.M. van

doi:10.1016/b978-0-12-024922-0.50008-4

Cited by 190 publications

(96 citation statements)

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“…It is clear that Ch absorption efficiency in animals shows considerable species variability. Rabbits and dogs absorb particularly large amounts of dietary Ch with a corresponding tendency toward diet-induced hypercholesterolemia (28,29,94). While generally demonstrating a dose-response relationship to Ch feeding, rats, monkeys, and humans absorb lower percentages of dietary Ch, and some primates, including humans, show considerable resistance to Ch feeding (94).…”

Section: Reevaluation Of Methods For Measurement Of Intestinal Ch Absmentioning

confidence: 99%

“…Rabbits and dogs absorb particularly large amounts of dietary Ch with a corresponding tendency toward diet-induced hypercholesterolemia (28,29,94). While generally demonstrating a dose-response relationship to Ch feeding, rats, monkeys, and humans absorb lower percentages of dietary Ch, and some primates, including humans, show considerable resistance to Ch feeding (94). Actually, mice are also highly resistant to Ch feeding in the natural state, and they have a more hydrophilic bile salt pool with, typically, equimolar amounts of T-␤-MC and TC (5,6,82,83).…”

Section: Reevaluation Of Methods For Measurement Of Intestinal Ch Absmentioning

confidence: 99%

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Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse: an analysis of direct versus indirect methodologies

Wang

Carey

2003

Journal of Lipid Research

133

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The rate of intestinal cholesterol (Ch) absorption is an important criterion for quantitation of Ch homeostasis. However, studies in the literature suggest that percent Ch absorption, measured usually by a fecal dual-isotope ratio method, spans a wide range, from 20% to 90%, in healthy inbred mice on a chow diet. In the present study, we adapted four standard methods, one direct (lymph collection) and three indirect (plasma and fecal dual-isotope ratio, and sterol balance) measurements of Ch absorption and applied them to mice. Our data establish that all methodologies can be valid in mice, with all methods supporting the concept that gallstone-susceptible C57L mice absorb significantly more Ch (37 ؎ 5%) than gallstone-resistant AKR mice (24 ؎ 4%). We ascertained that sources of error in the literature leading to marked differences in Ch absorption efficiencies between laboratories relate to a number of technical factors, most notably expertise in mouse surgery, complete solubilization and delivery of radioisotopes, appropriate collection periods for plasma and fecal samples, and total extraction of radioisotopes from feces. We find that all methods provide excellent interexperimental agreement, and the ranges obtained challenge previously held beliefs regarding the spread of intestinal Ch absorption efficiencies in mice. The approaches documented herein provide quantifiable methodologies for exploring genetic mechanisms of Ch absorption, and for investigating the assembly and secretion of chylomicrons, as well as intestinal lipoprotein metabolism in mice. The small intestine is the organ uniquely responsible for partial absorption of both dietary and biliary cholesterol (Ch), and plays a major role in regulation of wholebody Ch balance (1-3). Accurate and precise measurements of intestinal Ch absorption is one of the basic requirements for quantitation of Ch homeostasis as well as for ascertaining genetic variations and drug effects. Presently, there are three indirect methods available for measuring Ch absorption. Of these, the simplest is the plasma dual-isotope ratio method introduced by Zilversmit (4), recently modified by us for the mouse (5, 6). The method is based on the simultaneous ig and iv administration of [ 3 H]Ch and [ 14 C]Ch and measurement of plasma Ch isotope ratios at a set point in time: by definition, it assumes "100% absorption" of the iv dose. The most frequently employed method in the literature is the fecal dual-isotope ratio method (7), which is based on the administration of a single oral dose of radiolabled Ch and a nonabsorbed radiolabled phytosterol, such as ␤ -sitosterol (7,8) or sitostanol (9), as reference marker. The measurement is critically dependent on an accurate assessment of the ratios of excreted radioactivities of the two isotopes and their bacterial metabolites in feces. In a metabolic steady state, the sterol balance method (10-12) estimates the mass absorption of exogenous Ch based on the difference between dietary Ch and its fecal excretion. The measurement...

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Section: Reevaluation Of Methods For Measurement Of Intestinal Ch Absmentioning

confidence: 99%

Section: Reevaluation Of Methods For Measurement Of Intestinal Ch Absmentioning

confidence: 99%

Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse: an analysis of direct versus indirect methodologies

Wang

Carey

2003

Journal of Lipid Research

133

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“…However, when we repeated this trial 6 years later in the same volunteers with the same challenge and design [18], the correlation between an individual's response in the first and in the second study was only r = 0.32: many of the putative hyperresponders had become hyporesponders, and vice versa. The same was true for other cohorts of volunteers whom we tested repeatedly over the years [19][20][21][22]. Keys and coworkers [23], who studied one group of men on a variety of diets, also concluded that true non-responsiveness is rare if it exists at all, even though one subject may react aberrantly in one particular trial.…”

Section: Individual Responsiveness Is Partly a Statistical Artifactmentioning

confidence: 70%

The response of lipoproteins to dietary fat and cholesterol in lean and obese persons

Katan

2006

Current Cardiology Reports

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Individuals differ in the response of their blood lipoproteins to cholesterol-lowering diets. One characteristic clearly associated with susceptibility to diet is leanness: many studies show that total, LDL and HDL cholesterol concentrations respond more strongly to dietary fat and cholesterol in lean than in obese subjects. This is unlikely to be due differences in dietary compliance. A metabolic explanation is that obese people have a higher rate of total body cholesterol synthesis. The LDL receptors in their liver cells are partly suppressed by this large stream of endogenous cholesterol coming in from their enterohepatic circulation, and the amount added by dietary cholesterol relative to the endogenous pool would be less than in lean people.Whatever the mechanism, diets low in saturated fat and cholesterol are less effective in the obese; the most effective way for them to normalize their blood lipids is to lose weight, which is, unfortunately, hard to achieve in our society.

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“…It has been documented in numerous other species, including various nonhuman primate models and mice. 28,29 Although the basis for wide individual differences in sterol absorption is not well understood, genetic factors are apparently involved. 30 It is important that the underlying cause(s) of the high individual variability in cholesterol absorption be determined, because it may explain why some patients respond poorly, or not at all, to statins and other lipid-lowering drugs.…”

Section: Interpatient Variability In Cholesterol Absorptionmentioning

confidence: 99%

“…28,45 Higher levels of cholesterol absorption generally result in a suppression of cholesterol synthesis by the liver and an accumulation of cholesterol in the hepatocytes. 4 When a major pharmacologic block of cholesterol absorption is imposed, the diminished delivery of chylomicron cholesterol to the liver results in a partial compensatory upregulation of hepatic cholesterol synthesis.…”

Section: Rationale For Combining Cholesterol Absorption Inhibitors Wimentioning

confidence: 99%

Cholesterol metabolism and therapeutic targets: Rationale for targeting multiple metabolic pathways

Turley

2004

Clin Cardiol

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The liver is the major regulator of the plasma low density lipoprotein cholesterol (LDL‐C) concentration because it is not only the site of formation of very low density lipoproteins (VLDL), the precursors of most LDL in the circulation, but it is also the organ where the bulk of receptor‐mediated clearance of LDL takes place. The liver also initially clears all the cholesterol that is absorbed from the small intestine. The absorption of excess cholesterol can potentially increase the amount of cholesterol stored in the liver. This, in turn, can result in increased VLDL secretion, and hence LDL formation, and also downregulation of hepatic LDL receptor activity. Such events will potentially increase plasma LDL‐C levels. The converse situation occurs when cholesterol absorption is inhibited. Cholesterol enters the lumen of the small intestine principally from bile and diet. The major steps involved in the absorption process have been characterized. On average, about half of all cholesterol entering the intestine is absorbed, but the fractional absorption rate varies greatly among individuals. While the basis for this variability is not understood, it may partly explain why some patients respond poorly or not at all to statins and other classes of lipid‐lowering drugs. There are few data relating to racial differences in cholesterol absorption. One study reported a significantly higher rate in African Americans compared with non‐African Americans. Multiple lipid‐lowering drugs that target pathways involving the absorption, synthesis, transport, storage, catabolism, and excretion of cholesterol are available. Ezetimibe selectively blocks cholesterol absorption and lowers plasma LDL‐C levels by an average of 18%. When ezetimibe is coadministered with lower doses of statins, there is an additive reduction in LDL‐C level, which equals the reduction achieved with maximal doses of statins alone. Dual inhibition of cholesterol synthesis and absorption is an effective new strategy for treating hypercholesterolemia.

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Hypo- and Hyperresponders: Individual Differences in the Response of Serum Cholesterol Concentration to Changes in Diet

Cited by 190 publications

References 100 publications

Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse: an analysis of direct versus indirect methodologies

Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse: an analysis of direct versus indirect methodologies

The response of lipoproteins to dietary fat and cholesterol in lean and obese persons

Cholesterol metabolism and therapeutic targets: Rationale for targeting multiple metabolic pathways

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