LAUSR

Sitosterolemia (OMIM 210250) is a rare inherited autosomal recessive disorder of lipid metabolism, characterized by increased levels of plasma plant sterols (PS) such as stigmasterol, campesterol, and sitosterol [1,2]. Only around 100 patients with sitosterolemia have been reported so far, but the exact frequency of this disease is still unknown and maybe as high as 1 in 200,000 general population [1]. It is caused by molecular pathology in two genes named adenosine triphosphate-binding cassette (ABC) subfamily G members 5 and 8 (ABCG5 and ABCG8). These genes encode sterolin-1 or ABCG5 (651aa, UniProtKB-Q9H222) and sterolin-2 or ABCG8 (673aa, UniProtKB-Q9H221), respectively, which regulate the network of absorption and excretion of sitosterol and cholesterol [3]. ABCG5 and ABCG8 are ATP-binding cassette (ABC) half-transporters, which form an obligate heterodimer (ABCG5/ABCG8) able to move to the apical surface of cells and then to mediate Mg2+and ATP-dependent sterol transport across the cell membrane [4,5]. As other members of the ABC transporter family, its structure consists of an extracellular domain (ECD) that is in intimate contact with a compact transmembrane domain (TMD), which consists of six transmembrane helices (TMHs). The nucleotide-binding domain (NBD) is located N-terminal from the TMD and maintains a tightly closed dimer. At each NBDs, the ABC cassette and the TMD are in close proximity to a triple-helical bundle that consists of the connecting helix (CnH), the coupling helix (CpH) and the E-helix. The conserved Q-loop of ABC proteins is also located in this region. The triple-helical bundle may, therefore, serve as an immediate interface between TMD and NBD. The TMD polar relay is a cluster of polar amino acids located in the transmembrane segments and on the triple-helical bundles [5]. Despite the molecular mechanism by which ABCG5/ABCG8 effluxes sterol from plasma membranes remains to be elucidated, functional abnormalities in these proteins lead to the hyperabsorption and accumulation of PS in plasma [1–5]. Sitosterol is usually the most abundant PS in the diet, particularly in the Mediterranean diet, being present in vegetable oils, wheat germs, nuts, seeds, avocados, chocolate, and margarine. However, it is poorly absorbed (<5%) in healthy subjects [6]. High concentrations of PS in plasma and tissue proved extremely toxic in animal models and humans [5–7]. For this reason, the most frequent symptoms in sitosterolemia are metabolic and lipid abnormalities and premature cardiovascular disease (CVD) (Table I) [1,8–10]. These characteristics are shared with familial hypercholesterolemia (FH), a common disorder (1 in 200 general population), making it possible for sitosterolemia to be misdiagnosed as homozygous FH [8,11].