Incorporation of beta-sitosterol into the membrane increases resistance to oxidative stress and lipid peroxidation via estrogen receptor-mediated PI3K/GSK3beta signaling

Biochim Biophys Acta. 2013 Mar;1830(3):2538-44. doi: 10.1016/j.bbagen.2012.12.012.


Background: Brain lipid peroxidation has long been considered a potential therapeutic target for Alzheimer's disease (AD). beta-sitosterol (BS), a plant sterol that is prevalent in plant plasma membrane, has been suggested to have antioxidant activity. Previous studies have demonstrated that dietary BS can enter the brain and accumulates in the plasma membrane of brain cells. However, it is unknown whether and how BS exerts its antioxidant activity in plasma membrane.

Methods: To incorporate BS into the plasma membrane in vitro, HT22 cells and primarily cultured hippocampal cells were supplemented with BS using 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) as a carrier. The present study then tested the antioxidant effect of membrane BS against glucose oxidase (GOX)-induced oxidative stress and lipid peroxidation, and whether the antioxidant effect of membrane BS was associated with estrogen receptor (ER)-mediated phosphatidyl inositol 3-kinase (PL3K)/glycogen synthase kinase 3 (GSK3beta) signaling.

Results: Incorporation of BS into cell membrane prevented GOX-induced oxidative stress and lipid peroxidation, which could be suppressed by the ER antagonists and PI3K inhibitor. Additional experiments showed that incorporation of BS into cell membrane induced an up-regulation of PI3K activity and a recruitment of PI3K to lipid rafts, which could be inhibited by the ER antagonist. Membrane BS also increased the expression of p-GSK3beta, which could be suppressed in the presence of the ER antagonist and PI3K inhibitor.

General significance: Given that BS is prevalent in foods such as plant oil, the results provide a better understanding of the beneficial effects of these BS-enriched nutrients on neurodegenerative diseases such as AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Animals
  • Animals, Newborn
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Drug Carriers / chemistry
  • Gene Expression Regulation / drug effects
  • Glucose Oxidase / pharmacology
  • Glycogen Synthase Kinase 3 / genetics*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Primary Cell Culture
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Signal Transduction / drug effects*
  • Sitosterols / chemistry
  • Sitosterols / pharmacology*
  • beta-Cyclodextrins / chemistry


  • Antioxidants
  • Drug Carriers
  • Receptors, Estrogen
  • Sitosterols
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • gamma-sitosterol
  • Glucose Oxidase
  • Phosphatidylinositol 3-Kinases
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3