Current Therapy for Patients with Sitosterolemia –Effect of Ezetimibe on Plant Sterol Metabolism

Abstract

Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-binding cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy. J Atheroscler Thromb, 2010; 17:891-900.

A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing

“…The former mutation in the ABCG5 gene is one of the most common mutations among Asians with sitosterolemia 13) , while the latter mutation in the ABCG5 gene is considered novel. Meanwhile, both mutations in the MEFV gene identified in the proband are two of the most common mutations emia [17][18][19] . Careful monitoring and additional therapeutic approaches are needed to reduce her serum levels of sitosterol because of the unfavorable combination of hypersitosterolemia and systemic inflammatory disease, both of which have been shown to be associated with an increased risk of cardiovascular disease.…”

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

“…However, the full clinical spectrum of sitosterolaemia is likely not known due to under-reporting and/or underdiagnosis of the condition in patients with mild or no clinical features, such as the affected sibling of the proband 3) . Whether these patients, particularly those with normal plasma LDL-C levels, should receive long-term treatment to reduce the plasma sterol levels at an early age remains uncertain, although it has been reported that patients with sitosterolaemia have developed coronary heart disease after the plasma LDL-C, but not sterol, level was treated and controlled 21) . It is worth noting that the mother of the proband and the two affected sisters each exhibited elevated HDL-C levels, particularly the mother, who had a markedly elevated HDL-C level of 3.0 mmol/L, a value compatible with the complete loss of the (cholesteryl ester transfer protein) CETP activity 22) .…”

“…Previous case reports have suggested that sitosterolaemia is associated with rapidly progressive atherosclerosis and premature coronary heart disease, and the administration of effective long-term therapy is advised in such cases in order to halt the progression of atherosclerotic disease 20,21) . In the general population, there are conflicting data as to whether mild to moderately elevated plasma plant sterol levels are a risk factor for cardiovascular disease 7) .…”

“…Current therapies for sitosterolaemia, including bile acid sequestrants and ezetimibe, an NPC1L1 inhibitor, have moderate effects (20-50%) in reducing the levels of plasma sterols, and these parameters remain substantially elevated in most treated patients 9,21) . However, the plasma cholesterol levels are usually well controlled with ezetimibe.…”

Changes in Intestinal Gene Expression of Zebrafish (Danio rerio) Related to Sterol Uptake and Excretion upon β-Sitosterol Administration

“…In zebrafish, ApoA-I also contributes to sterol transporting system [18]. Excessive sterols are excreted out of the cells through the ATP-binding cassette sub-family G, member 5 and 8 (ABCG5 and ABCG8), back into the lumen in mammals [19]. Another ATP-binding cassette, sub-family A, member 1 (ABCA1), also exports sterols from the small intestinal epithelial cells into the circulation to contribute to the formation of HDL particles (Figure 1).…”