The National Lipid Association 2nd Annual Masters Summit: The Role of the Digestive Tract in Lipid Metabolism and CV Risk, November 3, 2007, Orlando, FL
Plant sterols and stanols: Their role in health and disease

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Abstract

Mammalian physiological processes, and likely any organism with a biliary tree, can distinguish between dietary cholesterol and noncholesterols, retaining very little of the noncholesterol in their bodies. Historically, the distinction between plant sterols and cholesterol has been known about for more than a century. That plants sterols are not “absorbed” has been investigated for almost half a century. The ingestion of plant sterols in gram quantities has been shown to interfere with cholesterol absorption and is one of the oldest pharmacologic therapies for hypercholesterolemia. Although the basis for the latter has been shown to be caused by exclusion of cholesterol from intestinal micelles by plant sterols, it was identification of a rare genetic disease, sitosterolemia, first described in 1974, that led to the hypothesis that specific molecular mechanism(s) governed both the entry and excretion of sterols by the body. This work will cover the physiology of dietary sterol metabolism, genetics, and pathophysiology of sitosterolemia. Additionally, the role of plant sterols in normal and abnormal metabolism in humans as well as selected animal models will be discussed.

Section snippets

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

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    This article was sponsored by educational grants from Merck/Schering-Plough, Daiichi Sankyo, Inc., and Unilever, Inc.

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