Abnormal high density lipoproteins in cerebrotendinous xanthomatosis

Area of Science:

• Biochemistry
• Genetics
• Cardiovascular Medicine

Background:

• Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder characterized by impaired bile acid synthesis.
• Patients with CTX often present with premature atherosclerosis and xanthomas despite normal or low plasma cholesterol levels.
• The role of high-density lipoproteins (HDL) in the pathophysiology of CTX remains incompletely understood.

Purpose of the Study:

• To characterize the plasma lipoprotein profiles, with a focus on HDL, in patients with CTX.
• To investigate potential links between HDL abnormalities and the increased atherogenesis observed in CTX.
• To explore the composition and apoprotein ratios of HDL in CTX patients.

Main Methods:

• Plasma lipoprotein analysis was performed on CTX patients.
• Quantification of HDL-cholesterol, lipid composition (cholesteryl esters, free cholesterol, phospholipids, triglycerides), and apoprotein ratios (apoAI/apoAII, apoC) in HDL.
• Morphological and particle size analysis of HDL using electron microscopy.

Main Results:

• CTX patients displayed significantly reduced HDL-cholesterol concentrations (14.5 +/- 3.2 mg/dl), approximately one-third of normal values.
• Plasma HDL in CTX showed decreased cholesteryl esters and increased triglycerides, with altered apoprotein composition (high apoAI/apoAII ratio, low apoC).
• HDL particles appeared morphologically normal in size and structure despite compositional abnormalities.

Conclusions:

• Abnormalities in HDL concentration and composition are a key feature of cerebrotendinous xanthomatosis.
• These HDL alterations likely contribute to the increased risk of atherogenesis and tissue sterol deposition in CTX.
• Metabolic defects linked to CTX's genetic basis may underlie the perturbed HDL function, impacting cholesterol homeostasis.