The National Lipid Association 2nd Annual Masters Summit: The Role of the Digestive Tract in Lipid Metabolism and CV Risk, November 3, 2007, Orlando, FLPlant sterols and stanols: Their role in health and disease
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Metabolism of cholesterol and plant sterols
The enterohepatic metabolism of cholesterol and plant sterols is complex (Fig. 2). The metabolic process occurs within the intestinal lumen, where dietary cholesterol (and plant sterols) is reduced to free sterols by esterases, and transferred into micelles (a mixture of bile salts, phospholipids, free sterols, and some fatty acids). These micelles interact with the enterocyte apical membrane (a process that has not been characterized at the molecular level) and allow entry of the sterols into
Sitosterolemia
A 22-year-old woman presented at the orthopedic clinic complaining of pain in both heels and knees. She had tendon xanthomas with a history of hand xanthomas beginning at age 8 years, which progressed to patellar, plantar, and Achilles tendon involvement. The patient has a sister with a similar phenotype. This combination of arthralgia and tendon xanthomas is associated with diagnosis of familial hypercholesterolemia. Familial hypercholesterolemia is characterized by hypercholesterolemia,
Plasma sterol profiles in sitosterolemia
Early work was undertaken to elucidate the mechanisms of sitosterolemia in individuals and families affected by the disorder.3, 12 Plasma sitosterol levels, measured by gas chromatography (GC) or high-pressure liquid chromatography (HPLC) in affected individuals, their obligate heterozygous parents, unaffected siblings, and normal controls were compared.13 Most unaffected individuals had plasma sitosterol levels <1 mg/dL (Fig. 4). Sitosterol levels >1 mg/dL in three parents and three siblings
Genetics of sitosterolemia
We performed linkage analyses of 10 well-characterized pedigrees and mapped the sitosterolemia locus, STSL, to human chromosome 2p21, between microsatellite markers D2S1788 and D2S1352.3, 12, 14 The disease locus interval was narrowed further and a physical map of this region constructed that allowed for positional cloning of the sitosterolemia “gene.”14
The surprise was that two highly homologous genes, adenosine triphosphate (ATP)–binding cassette (ABC)G5 and ABCG8, comprised the STSL locus
Pathophysiology of sitosterolemia
Once the gene defects were identified, it became possible to dissect the pathophysiology, using in vitro as well as animal models methodology. Absence of ABCG5, ABCG8, or both results in an elevation of plant sterols in the tissues and blood and a failure to excrete sterols into bile.24, 25, 26, 27, 28, 29, 30, 31 Overexpression of ABCG5 and ABCG8 in mice transgenic for the human genes led to a super saturation of cholesterol in bile and protected animals against atherosclerosis. Careful
Are there other clinical features that may indicate sitosterolemia?
A case was reported of a 19-year-old male who presented with chronic active liver disease and, after an extensive evaluation, was found to have sitosterolemia.34 Liver disease has not been reported to be feature in sitosterolemia. In contrast, diagnosis of “idiopathic cirrhosis” is not an uncommon diagnosis in people presenting with progressive liver failure. Because sitosterolemia requires analyses of blood by GC or HPLC for these sterols, it is possible that such cases are not diagnosed.
Plant sterol levels and normal physiology
The normal function of ABCG5 and ABCG8 genes is to limit intestinal absorption and promote the biliary excretion of neutral sterols, and in particular, limit noncholesterol sterols (xenosterols). Small but detectable levels of plant sterols can be found in all normal individuals, and these levels are very strongly influenced by genetic inheritance.37, 38 Common variations in ABCG5 or ABCG8 can contribute to wide interindividual variation in plasma concentrations of plant sterols among subjects
Are plant sterols a marker for premature atherosclerosis?
Glueck and colleagues were the first to report an association between serum phytosterol levels with a family history of coronary heart disease (CHD) in 595 hypercholesterolemic subjects.51 In a case-control study conducted in postmenopausal women, those with CAD had elevated ratios of squalene (P < 0.001), desmosterol (P = 0.005), campesterol (P = 0.028), and sitosterol (P = 0.022) to cholesterol, but had lower respective lathosterol values (P = 0.041) compared to the controls.52 After
Can we lower plant sterol levels?
A multicenter, double-blind, randomized, placebo-controlled study examined the effect of ezetimibe on reducing plant sterol levels in patients with sitosterolemia.57 Among 37 patients who were randomized to placebo or ezetimibe 10 mg/day for 8 weeks, sitosterol plasma levels decreased significantly (P < 0.001) with ezetimibe (−21% vs 4% increase with placebo). Campesterol levels also decreased significantly (P < 0.001) with ezetimibe (−24% with ezetimibe vs 3% increase with placebo). Total
Summary
Increased knowledge of the defective genes in sitosterolemia expands our understanding of this disease and has shed light into how we regulate dietary sterol absorption, sterol excretion, and keep xenosterols from accumulating in our bodies. This disease has led to the identification of the molecular players in a key physiological step and led to the identification of a previously unknown biochemical pathway that is essential to understanding whole-body sterol balance. Expanding knowledge of
References (58)
- et al.
Dietary cholesterol absorption; more than just bile
Trends Endocrin Metab
(2001) - et al.
Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis
J Lipid Res
(1998) - et al.
Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry
J Lipid Res
(1999) - et al.
Sitosterolemia
J Lipid Res
(1992) - et al.
Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis
J Lipid Res
(1989) - et al.
Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis
J Lipid Res
(1985) - et al.
Molecular cloning, genomic organization, genetic variations, and characterization of murine sterolin genes Abcg5 and Abcg8
J Lipid Res
(2002) - et al.
Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8 respectively
Am J Hum Genet
(2001) - et al.
ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion
J Biol Chem
(2003) - et al.
Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking
J Biol Chem
(2004)
Sterol transfer by ABCG5 and ABCG8: In vitro assay and reconstitution
J Biol Chem
Functional asymmetry of nucleotide-binding domains in ABCG5 and ABCG8
J Biol Chem
Sitosterolemia in ABC-Transporter G5-deficient mice is aggravated on activation of the liver-X receptor
Gastroenterology
Hepatic ABCG5 and ABCG8 overexpression increases hepatobiliary sterol transport but does not alter aortic atherosclerosis in transgenic mice
J Biol Chem
The mechanism of Abcg5/Abcg8 in biliary cholesterol secretion in mice
J Lipid Res
Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited
J Lipid Res
Response of obligate heterozygotes for phytosterolemia to a low-fat diet and to a plant sterol ester dietary challenge
J Lipid Res
Liver transplantation in a patient with sitosterolemia and cirrhosis
Gastroenterology
Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8
J Lipid Res
ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males
Clin Chim Acta
Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms?A preliminary study in siblings with gallstones
Eur J Intern Med
Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity
J Lipid Res
ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin
J Lipid Res
The ABCG5 polymorphism contributes to individual responses to dietary cholesterol and carotenoids in eggs
J Nutr
Single nucleotide polymorphisms in ABCG5 and ABCG8 are associated with changes in cholesterol metabolism during weight loss
J Lipid Res
Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives
Metabolism
Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women
J Am Coll Cardiol
Serum plant sterols as a potential risk factor for coronary heart disease
Metabolism
Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Münster (PROCAM) study
Nutr Metab Cardiovasc Dis
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This article was sponsored by educational grants from Merck/Schering-Plough, Daiichi Sankyo, Inc., and Unilever, Inc.