ABSTRACT
The large accumulation of plant sterols in blood and tissues in phytosterolemia is most likely related to three abnormal mechanisms: hyperabsorption and impaired biliary secretion of plant sterols, and reduced cholesterol synthesis. Healthy, normal humans
generally absorb 5% or less of ingested sitosterol, whereas phytosterolemic patients absorb extremely high levels; absorption rates ranging from 19% to 63% have been found in studies with phytosterolemic subjects (21,24,27,28). On the other hand, cholesterol absorption of phytosterolemic subjects seems normal (24). Recent molecular studies have identified the genetic defect in phytosterolemia and found that hyperabsorption of plant sterols is caused by mutations in either ABCG5 or ABCG8 genes located on chromosome 2p21, which normally control processes that act as an intestinal barrier for absorption of plant sterols and mediate their excretion from the liver (17,18,34). The higher absorption is accompanied by a defect in elimination of sterols in bile (24,32). Miettinen found that the biliary excretion of sitosterol in his patient was less than 20% of normal (24). There was also a low rate of biliary cholesterol excretion, which would decrease the intestinal dilution of plant sterol. Moreover, phytosterolemic patients have a reduced cholesterol 7α-hydroxylase activity, which is the rate-limiting step in bile acid synthesis (35). In two patients with phytosterolemia, the cholesterol 7α-hydroxylase activity was about 70% of the controls (35). The reduced activity is primarily due to inhibition of cholesterol 7αhydroxylase activity by the elevated levels of sitosterol and cholestanol as demonstrated by Shefer et al. in both rat and human liver microsomes (36). Furthermore, whole-body cholesterol synthesis is reduced in phytosterolemic subjects (24,27,32), and it has been suggested that high intracellular sterol pools (cholesterol+plant sterols) are detected by sterol sensors regulating cellular cholesterol homeostasis (37). Average cholesterol synthesis is about 50% lower in sitosterolemic subjects than in healthy controls (24,38,32). 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was also reduced in liver cell microsomes of patients with sitosterolemia as compared with controls (15 vs. 98pmol/mg protein/min) (38). Honda et al. (39) demonstrated that the reduced cholesterol synthesis in phytosterolemic subjects results from inhibition of all the enzymes mediating the cholesterol biosynthetic pathway, including HMG-CoA reductase, the rate-controlling enzyme for cholesterol biosynthesis in the liver and the mononuclear cells. Clearly, the increased absorption of sterols seen in phytosterolemia is primarily due to a functional mutation in a transporter that normally actively excludes plant sterols from the intestinal brush border and secretes into the bile. The lowering of HMG-CoA reductase activity might be due to down-regulation of the enzyme.
