Related Experiment Video

Updated: Aug 13, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity

Robert J Schmidt1, James V Ficorilli, Youyan Zhang

  • 1Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA.

Journal of Lipid Research
|January 18, 2006
PubMed

Insights

3beta-hydroxy-5alpha-cholest-8(14)-en-15-one (15-ketosterol) acts as a partial agonist for liver X receptors (LXRs), offering a molecular basis for its cholesterol-lowering effects and potential antiatherosclerotic benefits.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Hypercholesterolemia is a significant risk factor for coronary artery disease.
  • Oxysterols inhibit cholesterol biosynthesis and are investigated as antihypercholesterolemic agents.
  • The mechanism of action for 15-ketosterol's cholesterol-lowering effects is not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the hypocholesterolemic activity of 15-ketosterol.
  • To investigate 15-ketosterol's interaction with liver X receptors (LXRs).
  • To assess 15-ketosterol's effects on cholesterol metabolism pathways.

Main Methods:

  • Coactivator recruitment assays and cotransfection assays were used to determine LXR agonism.
  • Macrophage cell lines were used to assess ABCA1 mRNA expression.
  • HEK 293 cells were used to evaluate SREBP processing and downstream gene expression.

Main Results:

  • 15-ketosterol was identified as a partial agonist for liver X receptor-alpha and -beta (LXRα and LXRβ).
  • 15-ketosterol increased ATP binding cassette transporter ABCA1 mRNA in macrophages.
  • 15-ketosterol suppressed SREBP processing, inhibiting HMGCR, LDLR, and PCSK9 mRNA expression.

Conclusions:

  • The study provides a molecular basis for the hypocholesterolemic activity of 15-ketosterol.
  • 15-ketosterol demonstrates potential as an LXR agonist with antiatherosclerotic benefits.
  • These findings highlight 15-ketosterol as a promising therapeutic candidate for hypercholesterolemia.

Related Concept Videos

Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
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.
Considering cholesterol and...
Lipid-Lowering Drugs: Statins and Miscellaneous Agents01:20

Lipid-Lowering Drugs: Statins and Miscellaneous Agents

Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
Overview of Fatty Acid Metabolism01:28

Overview of Fatty Acid Metabolism

Lipids also are sources of energy that power cellular processes. Like carbohydrates, lipids are composed of carbon, hydrogen, and oxygen, but these atoms are arranged differently. Most lipids are nonpolar and hydrophobic. Major types include fats and oils, waxes, phospholipids, and steroids.
Fatty acids are catabolized in a process called beta-oxidation, which takes place in the matrix of the mitochondria and converts their fatty acid chains into two-carbon units of acetyl groups. The acetyl...
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...