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Cholesterol: Significance and Regulation01:29

Cholesterol: Significance and Regulation

Although not a source of energy, cholesterol plays a significant role as a foundational structure for bile salts, steroid hormones, and vitamin D, as well as being a crucial component of plasma membranes. Approximately 15% of blood cholesterol is derived from our diet, with the remainder synthesized from acetyl CoA by the liver and intestines. Cholesterol is eliminated from the body through its conversion into bile salts, which are eventually discarded in the feces.
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27-hydroxycholesterol is an endogenous selective estrogen receptor modulator.

Carolyn D DuSell1, Michihisa Umetani, Philip W Shaul

  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Molecular Endocrinology (Baltimore, Md.)
|September 18, 2007
PubMed
Summary

27-hydroxycholesterol (27HC), an endogenous molecule, acts as a selective estrogen receptor modulator (SERM). This oxysterol exhibits partial agonist activity in breast cancer cells, influencing cell proliferation and gene transcription.

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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Selective estrogen receptor modulators (SERMs) exhibit variable agonist/antagonist activities based on cell and promoter context.
  • The structural basis for SERM selectivity involves distinct alterations in estrogen receptor (ER) conformation, impacting coactivator/corepressor recruitment.
  • Oxysterols, such as 27-hydroxycholesterol (27HC), bind ER and may possess SERM activity, as suggested by their vascular effects.

Purpose of the Study:

  • To investigate whether 27-hydroxycholesterol (27HC), a prevalent oxysterol, functions as an endogenous selective estrogen receptor modulator (SERM).
  • To determine the specific effects of 27HC on estrogen receptor (ER) activity, gene transcription, and cell proliferation in breast cancer models.
  • To elucidate the structural basis for 27HC's unique interaction with ERalpha and ERbeta.

Main Methods:

  • Combinatorial peptide phage display was employed to analyze ER conformational changes induced by 27HC.
  • Cellular models of breast cancer were utilized to assess 27HC's impact on gene transcription and proliferation.
  • Comparative analysis of 27HC's structural effects on ERalpha and ERbeta versus 17beta-estradiol (E2) and other SERMs.

Main Results:

  • 27-hydroxycholesterol (27HC) was confirmed to function as a SERM with efficacy varying across different endpoints.
  • 27HC demonstrated partial agonist activity, promoting gene transcription and cell proliferation in breast cancer cellular models.
  • 27HC induces a unique conformational change in both ERalpha and ERbeta, distinct from E2 and other known SERMs.

Conclusions:

  • 27-hydroxycholesterol (27HC) is an endogenous SERM with partial agonist activity in breast cancer cells, potentially influencing breast cancer pathology.
  • The distinct structural alterations induced by 27HC in ER mediate its unique pharmacological activity and cofactor recruitment.
  • The findings suggest implications for breast cancer risk in individuals with obesity and hypercholesterolemia due to the cholesterol-27HC relationship.