Modulating insulin signaling and trafficking at the blood-brain barrier endothelium using lipid based nanoemulsions

Lushan Wang; Timothy S. Wiedmann; Karunya K. Kandimalla

doi:10.1016/j.ijpharm.2022.121823

Modulating insulin signaling and trafficking at the blood-brain barrier endothelium using lipid based nanoemulsions

Lushan Wang, Timothy S. Wiedmann, Karunya K. Kandimalla

Pharmaceutics

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1 Scopus citations

Abstract

The compositionally distinct lipid rafts present in the plasma membrane regulate the restrictive trafficking and signal transduction in the blood–brain barrier (BBB) endothelium. Several metabolic and neurodegenerative diseases are associated with lipid homeostasis disruption within the BBB endothelium. Here, we hypothesized that the delivery of lipid triglyceride based nanoemulsions containing unsaturated fatty acids (UFAs) provides a novel non-pharmacological approach to modulate lipid raft integrity and rectify the aberrant trafficking and signal transduction. The current study has shown that soybean oil nanoemulsions (SNEs) altered the morphology of lipid rafts that are stained by Alex Fluor 647 labelled cholera toxin (AF647-CTX) in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Moreover, western blot and flow cytometry analysis showed that SNEs containing polyunsaturated fatty acids (PUFAs) increased phospo-AKT (p-AKT) expression, a marker for the stimulation of metabolic arm of insulin signaling, and insulin uptake in hCMEC/D3 monolayers. However, olive oil nanoemulsions (ONEs) containing monounsaturated fatty acids (MUFAs) had no detectable impact on lipid raft integrity, AKT phosphorylation, or insulin uptake. These findings provided direct evidence that SNEs containing PUFAs can upregulate insulin-pAKT pathway, facilitate insulin trafficking at the BBB, and potentially address cerebrovascular dysfunction in metabolic and neurodegenerative diseases.

Original language	English (US)
Article number	121823
Journal	International journal of pharmaceutics
Volume	622
DOIs	https://doi.org/10.1016/j.ijpharm.2022.121823
State	Published - Jun 25 2022

Bibliographical note

Funding Information:
We thank Zhongfang Zhang and Xiaoyi Zhan from Shenyang Pharmaceutical University (Shenyang, Liaoning, China) for their assistance with preliminary investigation of nanoemulsion formulations. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. The authors also thank Mr. Jon E. Charlesworth, Mayo Clinic, Rochester, MN for the transmission electron micrographs. This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [MNP#15.31] and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS125437].

Funding Information:
We thank Zhongfang Zhang and Xiaoyi Zhan from Shenyang Pharmaceutical University (Shenyang, Liaoning, China) for their assistance with preliminary investigation of nanoemulsion formulations. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. The authors also thank Mr. Jon E. Charlesworth, Mayo Clinic, Rochester, MN for the transmission electron micrographs.

Funding Information:
This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [MNP#15.31] and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS125437].

Publisher Copyright:
© 2022

Keywords

Insulin resistance
Insulin signaling
Insulin trafficking
Lipid rafts
Nanoemulsions
Olive oil
Soybean oil
Unsaturated fatty acids

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijpharm.2022.121823

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title = "Modulating insulin signaling and trafficking at the blood-brain barrier endothelium using lipid based nanoemulsions",

abstract = "The compositionally distinct lipid rafts present in the plasma membrane regulate the restrictive trafficking and signal transduction in the blood–brain barrier (BBB) endothelium. Several metabolic and neurodegenerative diseases are associated with lipid homeostasis disruption within the BBB endothelium. Here, we hypothesized that the delivery of lipid triglyceride based nanoemulsions containing unsaturated fatty acids (UFAs) provides a novel non-pharmacological approach to modulate lipid raft integrity and rectify the aberrant trafficking and signal transduction. The current study has shown that soybean oil nanoemulsions (SNEs) altered the morphology of lipid rafts that are stained by Alex Fluor 647 labelled cholera toxin (AF647-CTX) in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Moreover, western blot and flow cytometry analysis showed that SNEs containing polyunsaturated fatty acids (PUFAs) increased phospo-AKT (p-AKT) expression, a marker for the stimulation of metabolic arm of insulin signaling, and insulin uptake in hCMEC/D3 monolayers. However, olive oil nanoemulsions (ONEs) containing monounsaturated fatty acids (MUFAs) had no detectable impact on lipid raft integrity, AKT phosphorylation, or insulin uptake. These findings provided direct evidence that SNEs containing PUFAs can upregulate insulin-pAKT pathway, facilitate insulin trafficking at the BBB, and potentially address cerebrovascular dysfunction in metabolic and neurodegenerative diseases.",

keywords = "Insulin resistance, Insulin signaling, Insulin trafficking, Lipid rafts, Nanoemulsions, Olive oil, Soybean oil, Unsaturated fatty acids",

author = "Lushan Wang and Wiedmann, {Timothy S.} and Kandimalla, {Karunya K.}",

note = "Funding Information: We thank Zhongfang Zhang and Xiaoyi Zhan from Shenyang Pharmaceutical University (Shenyang, Liaoning, China) for their assistance with preliminary investigation of nanoemulsion formulations. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. The authors also thank Mr. Jon E. Charlesworth, Mayo Clinic, Rochester, MN for the transmission electron micrographs. This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [MNP#15.31] and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS125437]. Funding Information: We thank Zhongfang Zhang and Xiaoyi Zhan from Shenyang Pharmaceutical University (Shenyang, Liaoning, China) for their assistance with preliminary investigation of nanoemulsion formulations. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. The authors also thank Mr. Jon E. Charlesworth, Mayo Clinic, Rochester, MN for the transmission electron micrographs. Funding Information: This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [MNP#15.31] and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS125437]. Publisher Copyright: {\textcopyright} 2022",

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AU - Kandimalla, Karunya K.

N1 - Funding Information: We thank Zhongfang Zhang and Xiaoyi Zhan from Shenyang Pharmaceutical University (Shenyang, Liaoning, China) for their assistance with preliminary investigation of nanoemulsion formulations. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. The authors also thank Mr. Jon E. Charlesworth, Mayo Clinic, Rochester, MN for the transmission electron micrographs. This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [MNP#15.31] and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS125437]. Funding Information: We thank Zhongfang Zhang and Xiaoyi Zhan from Shenyang Pharmaceutical University (Shenyang, Liaoning, China) for their assistance with preliminary investigation of nanoemulsion formulations. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. The authors also thank Mr. Jon E. Charlesworth, Mayo Clinic, Rochester, MN for the transmission electron micrographs. Funding Information: This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics [MNP#15.31] and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS125437]. Publisher Copyright: © 2022

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N2 - The compositionally distinct lipid rafts present in the plasma membrane regulate the restrictive trafficking and signal transduction in the blood–brain barrier (BBB) endothelium. Several metabolic and neurodegenerative diseases are associated with lipid homeostasis disruption within the BBB endothelium. Here, we hypothesized that the delivery of lipid triglyceride based nanoemulsions containing unsaturated fatty acids (UFAs) provides a novel non-pharmacological approach to modulate lipid raft integrity and rectify the aberrant trafficking and signal transduction. The current study has shown that soybean oil nanoemulsions (SNEs) altered the morphology of lipid rafts that are stained by Alex Fluor 647 labelled cholera toxin (AF647-CTX) in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Moreover, western blot and flow cytometry analysis showed that SNEs containing polyunsaturated fatty acids (PUFAs) increased phospo-AKT (p-AKT) expression, a marker for the stimulation of metabolic arm of insulin signaling, and insulin uptake in hCMEC/D3 monolayers. However, olive oil nanoemulsions (ONEs) containing monounsaturated fatty acids (MUFAs) had no detectable impact on lipid raft integrity, AKT phosphorylation, or insulin uptake. These findings provided direct evidence that SNEs containing PUFAs can upregulate insulin-pAKT pathway, facilitate insulin trafficking at the BBB, and potentially address cerebrovascular dysfunction in metabolic and neurodegenerative diseases.

AB - The compositionally distinct lipid rafts present in the plasma membrane regulate the restrictive trafficking and signal transduction in the blood–brain barrier (BBB) endothelium. Several metabolic and neurodegenerative diseases are associated with lipid homeostasis disruption within the BBB endothelium. Here, we hypothesized that the delivery of lipid triglyceride based nanoemulsions containing unsaturated fatty acids (UFAs) provides a novel non-pharmacological approach to modulate lipid raft integrity and rectify the aberrant trafficking and signal transduction. The current study has shown that soybean oil nanoemulsions (SNEs) altered the morphology of lipid rafts that are stained by Alex Fluor 647 labelled cholera toxin (AF647-CTX) in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Moreover, western blot and flow cytometry analysis showed that SNEs containing polyunsaturated fatty acids (PUFAs) increased phospo-AKT (p-AKT) expression, a marker for the stimulation of metabolic arm of insulin signaling, and insulin uptake in hCMEC/D3 monolayers. However, olive oil nanoemulsions (ONEs) containing monounsaturated fatty acids (MUFAs) had no detectable impact on lipid raft integrity, AKT phosphorylation, or insulin uptake. These findings provided direct evidence that SNEs containing PUFAs can upregulate insulin-pAKT pathway, facilitate insulin trafficking at the BBB, and potentially address cerebrovascular dysfunction in metabolic and neurodegenerative diseases.

KW - Insulin resistance

KW - Insulin signaling

KW - Insulin trafficking

KW - Lipid rafts

KW - Nanoemulsions

KW - Olive oil

KW - Soybean oil

KW - Unsaturated fatty acids

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Modulating insulin signaling and trafficking at the blood-brain barrier endothelium using lipid based nanoemulsions

Abstract

Bibliographical note

Keywords

UN SDGs

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