Cholesteryl lignocerate hydrolysis in adrenoleukodystrophy

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Disorders

Background:

• Very long chain fatty acids (VLCFAs) accumulate in Schilder adrenoleukodystrophy (ALD).
• Cholesteryl esters of VLCFAs are implicated in ALD pathogenesis.
• Understanding the hydrolysis of these esters is crucial for ALD research.

Purpose of the Study:

• To investigate the enzymatic activity responsible for hydrolyzing cholesteryl lignocerate, a VLCFA cholesteryl ester.
• To determine if this hydrolysis is impaired in fibroblasts from patients with Schilder adrenoleukodystrophy.

Main Methods:

• Assay of hydrolytic activity in fibroblast extracts using [14C]cholesteryl lignocerate.
• Testing the effect of pH and sulfhydryl inactivating agents on hydrolytic activity.
• Comparing hydrolytic activity in fibroblasts from ALD patients versus those with cholesteryl ester storage disease (CESD) or Wolman disease (WD).

Main Results:

• Hydrolytic activity for cholesteryl lignocerate was detected at pH 3.0.
• This activity was inhibited by sulfhydryl inactivating agents.
• Fibroblasts from CESD and WD patients showed deficient hydrolysis, consistent with acid lipase deficiency.
• Fibroblasts from ALD patients exhibited normal cholesteryl lignocerate hydrolysis.

Conclusions:

• The hydrolysis of cholesteryl lignocerate is likely mediated by acid lipase.
• Acid lipase function appears to be intact in Schilder adrenoleukodystrophy fibroblasts.
• This finding differentiates the enzymatic defect in ALD from primary acid lipase deficiencies like CESD and WD.