Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Abstract

Using plasma isotope-kinetic methods, we measured the absorption and turnover rates of cholesterol and sitosterol (24-ethylcholesterol) in two obligate heterozygotes (parents) and their homozygous daughter with sitosterolemia with xanthomatosis. Diets contained approximately 500 mg/day cholesterol and 100 mg/day sitosterol. In the homozygote, plasma cholesterol and apolipoprotein B concentrations were slightly higher, but sitosterol levels were 22 and 58 times higher than in her heterozygous parents. Cholesterol absorption was at the high end of the normal range in both heterozygotes (59% and 84%) and in the homozygote (62%) (value in the control subject 48%). In contrast, cholesterol synthesis was severely depressed in the homozygote (28% and 26% as great as in the heterozygotes and the control, respectively). Sitosterol absorption in the homozygote (34%) was 12 and 2.0 times greater than in the heterozygotes and 6.8 times greater than in the control. The sitosterol turnover rate, calculated independently by mathematical analysis of specific-activity decay curves, amounted to 15 and 24 mg/day in the heterozygotes compared with 27 mg/day in the homozygote and 7.9±2J mg/day in five control subjects. However, the total body sitosterol pool was 15 and 103 times larger in the homozygote (4,080 mg) than in her heterozygous parents because of extremely slow removal. The average sitosterol elimination constant in the heterozygotes (K A =0.11 day" 1 ) was 10 times that in the homozygote (K A =0.01 day" 1 ) but 35% less than that in the controls (K A =0.17 day" 1 ). These results demonstrate that despite enhanced sitosterol absorption, small body pools and low plasma concentrations result from rapid elimination associated with adequate cholesterol synthesis in sitosterolemic heterozygotes. In distinction, sitosterol accumulates and body pools are disproportionately enlarged because increased absorption is combined with decreased removal, which may compensate for reduced cholesterol synthesis in sitosterolemic homozygotes. S itosterolemia with xanthomatosis is a rare lipid storage disease that presents clinically with accelerated atherosclerosis, tendon and tuberous xanthomas, hemotysis, and symmetrical arthritis and arthralgias involving the ankle and knee joints.1 Increased amounts of plant sterols (sitosterol, campesterol, and stigmasterol) and 5a-stanols (cholestanol, 5a-sitostanol, and 5a-campestanol) are present in plasma and all tissues except brain.2 Enhanced absorption of sitosterol and structurally related sterols has been suggested to account for the enlarged pools, 3 -7 while cholestanol and 5o-saturated plant sterol derivatives are produced endogenousry because diets are virtually devoid of these stanols. 8 - 10 The disease isFrom the Veterans Administration Medical Center, East Orange, and the University of Medicine and Dentistry-New Jersey Medical College, Newark, NJ.Supported by Research Service, Veterans Administration, and US Public Health Service grants HL-17818, DK-18707, and DK-26756.Address for c...

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

“…ACAT-2 acyl-CoA: cholesterol acyltransferase-2, Chol cholesterol, MTP microsomal triglyceride transfer protein, MRP2 multidrug resistance-associated protein 2 (ABCC2), NTCP sodium taurocholate cotransporting polypeptide, PL phospholipids, SR-B1 scavenger receptor B1. Adapted from Lu et al [38], copyright 2001 with permission from Elsevier cholesterol when these are directly infused into their veins [51]. Studies in knockout mice confirm that this response, at least for biliary sterol secretion, is mediated by Abcg5/ Abcg8 and is increased by Lxr activation [67].…”

Similar serum plant sterol responses of human subjects heterozygous for a mutation causing sitosterolemia and controls to diets enriched in plant sterols or stanols

“…Although phytosterols and cholesterol are absorbed by the same principle mechanism, it is remarkable that the absorption rates for plant sterols and their hydrogenated derivatives, stanols, are much lower than those for cholesterol (Salen et al, 1992b;Heinemann et al, 1993;Ostlund et al, 2002). This is owing to the action of two half-transporters, ATP-binding cassette transporters (ABC) G5 and G8, which form a heterodimer located in the apical cell membranes of enterocytes that is capable of pumping plant sterols and stanols back into the intestinal lumen once they have been taken up .…”

Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion inAbcg8−/− mice

“…1 Sitosterolemic patients display hyperabsorption of cholesterol and phytosterols and reduced secretion of these sterols into bile. 2,3 Patel et al 4 were the first to map the sitosterolemia locus, STSL, to human chromosome 2p21, between D2S2294 and D2S2298. Using a positional cloning approach as well as microarray analysis of murine complementary DNAs from intestines and livers of mice treated with a liver X receptor (LXR) agonist, 2 groups 5,6 independently identified the adjacent genes, ABCG5 and ABCG8, encoding adenosine triphosphatebinding cassette (ABC) hemi-transporters that are mutated in sitosterolemia.…”

“…In a study where cholesterol absorption was measured by a fecal dual-isotope ratio method in Abcg5 Ϫ/Ϫ /Abcg8 Ϫ/Ϫ mice, sitostanol was employed injudiciously as the "nonabsorbable" standard for correction 10 because it is absorbed well in humans with sitosterolemia. [1][2][3] In addition, the difficult and laborious biliary sterol secretion studies in humans pose a dilemma, because patients with mutations in either ABCG5 or ABCG8 are rare and geographically scattered. Despite the aforementioned studies and issues, little information is available to date on whether ABCG5 alone, ABCG8 alone, or both ABCG5 and ABCG8 are responsible for selectively pumping cholesterol and sitostanol out of enterocytes and hepatocytes and whether the 2 half-transporters function as homodimers or heterodimers.…”