Investigating sitosterolemia to understand lipid physiology

Abstract

Summary The cholesterol molecule is at the center of the pathophysiology of many vascular diseases. Whole-body cholesterol pools are maintained by a balance of endogenous synthesis, dietary absorption and elimination from our bodies. While the cellular aspects of cholesterol metabolism received significant impetus from the seminal work of Goldstein and Brown investigating LDL receptor trafficking, how dietary cholesterol was absorbed and eliminated was relatively neglected. The identification of the molecular defect a rare human disorder, Sitosterolemia, led to elucidation of a key mechanism of how we regulate the excretory pathway in the liver and in the intestine. Two proteins, ABCG5 and ABCG8, constitute a heterodimeric transporter that facilitates the extrusion of sterols from the cell into the biliary lumen, with a preference for xenosterols. This mechanism explained how dietary xenosterols are prevented from accumulating in our bodies. In addition, this disease has also highlighted the potential harm of xenosterols; macrothrombocytopenia, liver disease and endocrine disruption are seen when xenosterols accumulate. Mouse models of this disease suggest that there are more dramatic alterations of physiology, suggesting that these highly conserved mechanisms have evolved to prevent these xenosterols from accumulating in our bodies.

Kinetics of phytosterol metabolism in neonates receiving parenteral nutrition

“…Two proteins, ABCG5 and ABCG8, have been identified as key regulators of phytosterols. Both are found in apical membranes of the small intestine and liver where they serve as sterol export pumps to prevent phytosterol accumulation in the body ( 17 , 18 ). In normal individuals who consume phytosterols in their diet, low plasma phytosterol concentrations are primarily due to intestinal ABCG5/G8 that prevent their absorption ( 13 ).…”

Importance of Cholesterol Side Chain in the Membrane Stability of Human Erythrocytes

“…31) Absorption of plant sterols from intestine is suppressed in healthy individual. 32) However, plasma concentrations of plant sterols are elevated in Sitosterolemia. 33) Such patients are subjected to a risk of cardiovascular disease.…”

“…32) However, plasma concentrations of plant sterols are elevated in Sitosterolemia. 33) Such patients are subjected to a risk of cardiovascular disease. 31) The present work also suggests the increased risk of hemolysis under stresses if the erythrocyte membrane is loaded with plant sterols.…”

Potential Hepatotoxicities of Intravenous Fat Emulsions in Infants and Children

“…Similar to cholesterol, phytosterols are important components of cell membranes. Phytosterols can displace cholesterol from liver microsomal membranes and the alkylated side chains of phytosterols make them more effective than cholesterol at ordering the phospholipid bilayer to reduce the fluidity of cell membranes 46 …”

“…Phytosterols can displace cholesterol from liver microsomal membranes and the alkylated side chains of phytosterols make them more effective than cholesterol at ordering the phospholipid bilayer to reduce the fluidity of cell membranes. 46 The evidence for the hepatotoxicity of soy lipid-derived phytosterols has been demonstrated in humans and laboratory models. In clinical studies, phytosterols accumulate in patients with IFALD, and elevated phytosterol levels have been correlated with disease severity in infants and children with prolonged PN.…”