Beneficial effects of β-sitosterol on type 1 cholecystokinin receptor dysfunction induced by elevated membrane cholesterol

Aditya J. Desai, Maoqing Dong, Laurence J Miller

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background & aims: The type 1 cholecystokinin receptor (CCK1R) mediates the actions of CCK to support nutritional homeostasis, including post-cibal satiety. However, elevated levels of membrane cholesterol, such as have been observed in metabolic syndrome, interfere with CCK stimulus-activity coupling at the CCK1R, thereby disrupting this important servomechanism. We hypothesize that reversal of the negative impact of cholesterol on this receptor could be useful in the management of obesity. Methods: We have studied the effects of β-sitosterol, a phytosterol structurally related to cholesterol, on CCK receptor function. This included CCK binding and biological activity at wild type CCK1R and CCK2R, as well as at CCK1R in a high cholesterol environment, and at a CCK1R mutant, Y140A, which mimics the behavior of wild type receptor in high cholesterol. Results: β-sitosterol (100 μM and 10 μM) significantly improved the defective signaling of the CCK1R present in high cholesterol (p <0.05), without affecting CCK binding affinity. This effect was absent at the CCK1R present in a normal cholesterol environment, as well as at the structurally-related CCK2R. Furthermore, the cholesterol-insensitive Y140A mutant of CCK1R was resistant to the effects of β-sitosterol. Conclusion: These data suggest that β-sitosterol affects CCK1R function in high cholesterol by competing with cholesterol at a receptor cholesterol-binding site and may shift its conformation toward normal. This phytosterol extends our understanding of the structure-activity relationships for developing a drug that can target the external surface of CCK1R. Since the concentrations of β-sitosterol shown to be effective in this study are similar to serum levels of this compound achievable during oral administration, it may be worthwhile to study possible beneficial effects of β-sitosterol in metabolic syndrome.

Original languageEnglish (US)
JournalClinical Nutrition
DOIs
StateAccepted/In press - Sep 10 2015

Fingerprint

Cholecystokinin Receptors
Hypercholesterolemia
Cholesterol
Membranes
Phytosterols
gamma-sitosterol
Nutritional Support
Structure-Activity Relationship
Oral Administration
Homeostasis
Obesity

Keywords

  • Cholecystokinin receptor
  • Cholesterol
  • Metabolic syndrome
  • Phytosterols

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Nutrition and Dietetics

Cite this

@article{937dee5f947e43a7bfa9d3f8b1a56c5d,
title = "Beneficial effects of β-sitosterol on type 1 cholecystokinin receptor dysfunction induced by elevated membrane cholesterol",
abstract = "Background & aims: The type 1 cholecystokinin receptor (CCK1R) mediates the actions of CCK to support nutritional homeostasis, including post-cibal satiety. However, elevated levels of membrane cholesterol, such as have been observed in metabolic syndrome, interfere with CCK stimulus-activity coupling at the CCK1R, thereby disrupting this important servomechanism. We hypothesize that reversal of the negative impact of cholesterol on this receptor could be useful in the management of obesity. Methods: We have studied the effects of β-sitosterol, a phytosterol structurally related to cholesterol, on CCK receptor function. This included CCK binding and biological activity at wild type CCK1R and CCK2R, as well as at CCK1R in a high cholesterol environment, and at a CCK1R mutant, Y140A, which mimics the behavior of wild type receptor in high cholesterol. Results: β-sitosterol (100 μM and 10 μM) significantly improved the defective signaling of the CCK1R present in high cholesterol (p <0.05), without affecting CCK binding affinity. This effect was absent at the CCK1R present in a normal cholesterol environment, as well as at the structurally-related CCK2R. Furthermore, the cholesterol-insensitive Y140A mutant of CCK1R was resistant to the effects of β-sitosterol. Conclusion: These data suggest that β-sitosterol affects CCK1R function in high cholesterol by competing with cholesterol at a receptor cholesterol-binding site and may shift its conformation toward normal. This phytosterol extends our understanding of the structure-activity relationships for developing a drug that can target the external surface of CCK1R. Since the concentrations of β-sitosterol shown to be effective in this study are similar to serum levels of this compound achievable during oral administration, it may be worthwhile to study possible beneficial effects of β-sitosterol in metabolic syndrome.",
keywords = "Cholecystokinin receptor, Cholesterol, Metabolic syndrome, Phytosterols",
author = "Desai, {Aditya J.} and Maoqing Dong and Miller, {Laurence J}",
year = "2015",
month = "9",
day = "10",
doi = "10.1016/j.clnu.2016.03.003",
language = "English (US)",
journal = "Clinical Nutrition",
issn = "0261-5614",
publisher = "Churchill Livingstone",

}

TY - JOUR

T1 - Beneficial effects of β-sitosterol on type 1 cholecystokinin receptor dysfunction induced by elevated membrane cholesterol

AU - Desai, Aditya J.

AU - Dong, Maoqing

AU - Miller, Laurence J

PY - 2015/9/10

Y1 - 2015/9/10

N2 - Background & aims: The type 1 cholecystokinin receptor (CCK1R) mediates the actions of CCK to support nutritional homeostasis, including post-cibal satiety. However, elevated levels of membrane cholesterol, such as have been observed in metabolic syndrome, interfere with CCK stimulus-activity coupling at the CCK1R, thereby disrupting this important servomechanism. We hypothesize that reversal of the negative impact of cholesterol on this receptor could be useful in the management of obesity. Methods: We have studied the effects of β-sitosterol, a phytosterol structurally related to cholesterol, on CCK receptor function. This included CCK binding and biological activity at wild type CCK1R and CCK2R, as well as at CCK1R in a high cholesterol environment, and at a CCK1R mutant, Y140A, which mimics the behavior of wild type receptor in high cholesterol. Results: β-sitosterol (100 μM and 10 μM) significantly improved the defective signaling of the CCK1R present in high cholesterol (p <0.05), without affecting CCK binding affinity. This effect was absent at the CCK1R present in a normal cholesterol environment, as well as at the structurally-related CCK2R. Furthermore, the cholesterol-insensitive Y140A mutant of CCK1R was resistant to the effects of β-sitosterol. Conclusion: These data suggest that β-sitosterol affects CCK1R function in high cholesterol by competing with cholesterol at a receptor cholesterol-binding site and may shift its conformation toward normal. This phytosterol extends our understanding of the structure-activity relationships for developing a drug that can target the external surface of CCK1R. Since the concentrations of β-sitosterol shown to be effective in this study are similar to serum levels of this compound achievable during oral administration, it may be worthwhile to study possible beneficial effects of β-sitosterol in metabolic syndrome.

AB - Background & aims: The type 1 cholecystokinin receptor (CCK1R) mediates the actions of CCK to support nutritional homeostasis, including post-cibal satiety. However, elevated levels of membrane cholesterol, such as have been observed in metabolic syndrome, interfere with CCK stimulus-activity coupling at the CCK1R, thereby disrupting this important servomechanism. We hypothesize that reversal of the negative impact of cholesterol on this receptor could be useful in the management of obesity. Methods: We have studied the effects of β-sitosterol, a phytosterol structurally related to cholesterol, on CCK receptor function. This included CCK binding and biological activity at wild type CCK1R and CCK2R, as well as at CCK1R in a high cholesterol environment, and at a CCK1R mutant, Y140A, which mimics the behavior of wild type receptor in high cholesterol. Results: β-sitosterol (100 μM and 10 μM) significantly improved the defective signaling of the CCK1R present in high cholesterol (p <0.05), without affecting CCK binding affinity. This effect was absent at the CCK1R present in a normal cholesterol environment, as well as at the structurally-related CCK2R. Furthermore, the cholesterol-insensitive Y140A mutant of CCK1R was resistant to the effects of β-sitosterol. Conclusion: These data suggest that β-sitosterol affects CCK1R function in high cholesterol by competing with cholesterol at a receptor cholesterol-binding site and may shift its conformation toward normal. This phytosterol extends our understanding of the structure-activity relationships for developing a drug that can target the external surface of CCK1R. Since the concentrations of β-sitosterol shown to be effective in this study are similar to serum levels of this compound achievable during oral administration, it may be worthwhile to study possible beneficial effects of β-sitosterol in metabolic syndrome.

KW - Cholecystokinin receptor

KW - Cholesterol

KW - Metabolic syndrome

KW - Phytosterols

UR - http://www.scopus.com/inward/record.url?scp=84962200766&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962200766&partnerID=8YFLogxK

U2 - 10.1016/j.clnu.2016.03.003

DO - 10.1016/j.clnu.2016.03.003

M3 - Article

JO - Clinical Nutrition

JF - Clinical Nutrition

SN - 0261-5614

ER -