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Cholesterol, hydroxycholesterols, and bile acids.

Norman B Javitt1

  • 1New York University School of Medicine, New York, NY 10016, USA. Norman.Javitt@med.nyu.edu

Biochemical and Biophysical Research Communications
|April 24, 2002
PubMed
Summary

Enzyme-catalyzed cholesterol oxidation occurs at five specific sites. These hydroxycholesterols and their metabolites impact cholesterol synthesis, nuclear receptor signaling, and bile acid production, with distinct roles in different life stages.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Cholesterol oxidation products are numerous in vitro, but enzyme-catalyzed oxidations are site-specific (C7α, C22R, C24S, C25, C27).
  • Understanding these specific oxidation pathways is crucial for comprehending cholesterol metabolism and its broader biological implications.

Purpose of the Study:

  • To clone genes for cholesterol-oxidizing enzymes, identify tissue mRNA expression, and characterize enzyme properties.
  • To investigate the biological properties of generated hydroxycholesterols and their metabolites.
  • To elucidate the role of hydroxycholesterols as ligands for the nuclear receptor LXRα and their impact on gene expression.

Main Methods:

  • Gene cloning and characterization of enzymes involved in cholesterol oxidation.

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  • Identification of tissue-specific mRNA expression patterns for these enzymes.
  • Analysis of hydroxycholesterol and metabolite biological activities, including effects on cholesterol synthesis and LXRα signaling.

    • Main Results:

    • Common downregulation of cholesterol synthesis via SREBP/SCAP pathway by initial hydroxycholesterols.
    • Varied roles as LXRα ligands, influencing cholesterol 7α-hydroxylase and ABC transporter expression.
    • Metabolism of 22S-hydroxycholesterol yields steroid hormones, while others produce bile acids; 24S and 25-hydroxycholesterols contribute <7% to daily bile acid production in adults.

    Conclusions:

    • Cholesterol 7α-hydroxycholesterol from the liver is a primary source of bile acids in older adults.
    • The cholesterol 27-hydroxylation pathway is essential in fetal and neonatal life.
    • Further research is needed to determine the shift in metabolic pathway contributions to bile acid synthesis and the role of cholesterol 27-hydroxylase in reverse cholesterol transport.