What is the role of reduced cholesterol synthesis in the pathophysiology of sitosterolemia (phytosterolemia)?

Updated: May 24, 2019
  • Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Sitosterolemia was originally thought to be associated with a single inherited defect in the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase gene, but more recent studies suggest that inadequate cholesterol production in sitosterolemia is due to abnormal down-regulation of early, intermediate, and late enzymes in the cholesterol biosynthetic pathway.

Patients have markedly reduced whole-body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte HMG-CoA reductase, the rate-controlling enzyme in the cholesterol biosynthetic pathway.

Whether or not the down-regulation is due to accumulated sitosterol is still debatable, but most recent data indicate that secondary effects of unknown regulators other than sitosterol can lead to reduced HMG-CoA reductase activity in the disease. This is coupled with significantly increased LDL receptor expression.

The precise relationship between enhanced sterol absorption, hepatic sterol retention, and down-regulation of cholesterol biosynthesis underlying the disorder remains unknown; however, identification of these processes as characteristics of the disorder has led to viable treatment options.

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