Dietary cholesterol absorption

In the early 1970s, Bhattacharyya and Connor studied two sisters who complained of arthralgias, and had tendon xanthomas and haemolytic anaemia. The doctors recognised the symptoms as those of autosomal dominant familial hypercholesterolaemia. However, neither girl had raised concentrations of blood cholesterol—a classic sign of the disease. Furthermore, neither of the sisters’ parents had the disorder, suggesting autosomal recessive inheritance. After assessing the girls, Bhattacharyya and Connor wrote a seminal paper, published in 1974, in which they identified the cause of the newly identified disorder as raised concentrations of plant sterols. And since sitosterol was the major plant sterol present in the sisters’ blood, they named the disease sitosterolaemia. The disorder is not well recognised by the general medical community, or by many lipid specialists. The true prevalence is thus unknown, although more than 50 families worldwide have been reported in medical publications. A standard cholesterol test cannot distinguish between cholesterol and non-cholesterol sterols, and a specialised test (gas-liquid or high performance liquid chromatography analyses) therefore has to be done to confirm the diagnosis. The disease is associated with an increased cardiovascular risk, as highlighted by the presentation some years ago of two men, not yet 20 years old, who had fatal heart attacks. Subsequent investigation of their families led to a diagnosis of sitosterolaemia among their relatives. Although a formal study of the prevalence of premature atherosclerotic disease has not been published, we have followed up more than 34 families with a history of sitosterolaemia, and more than half have documented atherosclerotic disease. The identification of sitosterolaemia has focused attention on the basic processes that govern how we normally absorb dietary cholesterol and keep all other sterols out. Our diets generally contain about equal amounts of cholesterol and plant sterols. Plants do not make cholesterol, but use molecules that are similar, such as sitosterol. Under normal circumstances, our bodies do not retain any of these non-cholesterol sterols and, on average, we absorb about 55% of dietary cholesterol. Thus, in healthy individuals, there exists an exquisite mechanism that allows the body to distinguish between sterols. The genetic defect in sitosterolaemia has been identified. Human beings have two genes located in a head-to-head configuration, a mutation in either of which results in sitosterolaemia. ABCG5 and ABCG8, and the proteins that they encode (sterolin-1 and sterolin-2, respectively) are highly homologous to each other and might have arisen through gene duplication during evolution. These genes are part of a larger ABC family of proteins, characterised by the presence of an ATP-binding cassette motif. Better known members of this family are the cystic fibrosis transconductance regulator, the sulphonylurea receptor, and the multidrug resistance proteins. Sterolins are expressed in the intestine and the liver only. Sterolin-1 and sterolin-2 work together to exclude non-cholesterol sterols from our bodies, probably by preventing initial entry at the intestinal level, and by rapidly excreting any residual amounts that enter the bloodstream, by rapid uptake by the liver and excretion into bile (figure). Findings of genetic studies also suggest that some of the mutations that cause sitosterolaemia might be old; analyses of the Amish-Mennonite community indicate that their mutation might have been brought from Europe to the Americas around the late 1700s. Genetic analyses of other families suggest that some mutations occurred more than 1800 years ago. Cholesterol, once synthesised or absorbed, can only be disposed of by the body via the bile system, either by direct excretion or by breakdown into bile acids. Enterohepatic circulation is therefore involved in the removal of cholesterol. Statin drugs (simvastatin, atorvastatin, &c) are potent inhibitors of cholesterol synthesis. A more effective therapy for reducing raised concentrations of cholesterol might also affect loss of cholesterol. Although not proven, sterolins in the liver could be responsible for the direct excretion of cholesterol into bile. Cholesterol is an important molecule for normal embryonic development, but can also be a potent risk factor for heart disease in later life. A greater understanding of the mechanisms involved in its metabolism would not only result in treatment options for sitosterolaemia, but would also lead to a greater understanding of the processes of cholesterol absorption and excretion in the general population. Dietary sterol absorption and the sites of defects in sitosterolaemia