Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes

Sugata Hazra; Adil Rasheed; Ashay Bhatwadekar; Xiaoxin Wang; Lynn C. Shaw; Monika Patel; Sergio Caballero; Lilia Magomedova; Nathaniel Solis; Yuanqing Yan; Weidong Wang; Jeffrey S. Thinschmidt; Amrisha Verma; Qiuhong Li; Moshe Levi; Carolyn L. Cummins; Maria B. Grant

doi:10.2337/db11-1596

Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes

Sugata Hazra, Adil Rasheed, Ashay Bhatwadekar, Xiaoxin Wang, Lynn C. Shaw, Monika Patel, Sergio Caballero, Lilia Magomedova, Nathaniel Solis, Yuanqing Yan, Weidong Wang, Jeffrey S. Thinschmidt, Amrisha Verma, Qiuhong Li, Moshe Levi, Carolyn L. Cummins^*, Maria B. Grant

^*Corresponding author for this work

Surgery, Thoracic Surgery Division

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of "cholesterol-sensing" nuclear receptors, the liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetesinduced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXRα ^-/-, LXRβ^-/-, and LXRα/β^-/- mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXRα^-/-, LXRβ^-/-, and LXRα/β^-/- mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction.

Original language	English (US)
Pages (from-to)	3270-3279
Number of pages	10
Journal	Diabetes
Volume	61
Issue number	12
DOIs	https://doi.org/10.2337/db11-1596
State	Published - Dec 2012

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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Hazra, S., Rasheed, A., Bhatwadekar, A., Wang, X., Shaw, L. C., Patel, M., Caballero, S., Magomedova, L., Solis, N., Yan, Y., Wang, W., Thinschmidt, J. S., Verma, A., Li, Q., Levi, M., Cummins, C. L., & Grant, M. B. (2012). Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes. Diabetes, 61(12), 3270-3279. https://doi.org/10.2337/db11-1596

@article{a148e1c7d5b74b76ba091a6919df2b2a,

title = "Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes",

abstract = "Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of {"}cholesterol-sensing{"} nuclear receptors, the liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetesinduced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXRα -/-, LXRβ-/-, and LXRα/β-/- mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXRα-/-, LXRβ-/-, and LXRα/β-/- mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction.",

author = "Sugata Hazra and Adil Rasheed and Ashay Bhatwadekar and Xiaoxin Wang and Shaw, {Lynn C.} and Monika Patel and Sergio Caballero and Lilia Magomedova and Nathaniel Solis and Yuanqing Yan and Weidong Wang and Thinschmidt, {Jeffrey S.} and Amrisha Verma and Qiuhong Li and Moshe Levi and Cummins, {Carolyn L.} and Grant, {Maria B.}",

year = "2012",

month = dec,

doi = "10.2337/db11-1596",

language = "English (US)",

volume = "61",

pages = "3270--3279",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

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Hazra, S, Rasheed, A, Bhatwadekar, A, Wang, X, Shaw, LC, Patel, M, Caballero, S, Magomedova, L, Solis, N, Yan, Y, Wang, W, Thinschmidt, JS, Verma, A, Li, Q, Levi, M, Cummins, CL & Grant, MB 2012, 'Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes', Diabetes, vol. 61, no. 12, pp. 3270-3279. https://doi.org/10.2337/db11-1596

TY - JOUR

T1 - Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes

AU - Hazra, Sugata

AU - Rasheed, Adil

AU - Bhatwadekar, Ashay

AU - Wang, Xiaoxin

AU - Shaw, Lynn C.

AU - Patel, Monika

AU - Caballero, Sergio

AU - Magomedova, Lilia

AU - Solis, Nathaniel

AU - Yan, Yuanqing

AU - Wang, Weidong

AU - Thinschmidt, Jeffrey S.

AU - Verma, Amrisha

AU - Li, Qiuhong

AU - Levi, Moshe

AU - Cummins, Carolyn L.

AU - Grant, Maria B.

PY - 2012/12

Y1 - 2012/12

N2 - Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of "cholesterol-sensing" nuclear receptors, the liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetesinduced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXRα -/-, LXRβ-/-, and LXRα/β-/- mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXRα-/-, LXRβ-/-, and LXRα/β-/- mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction.

AB - Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of "cholesterol-sensing" nuclear receptors, the liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetesinduced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXRα -/-, LXRβ-/-, and LXRα/β-/- mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXRα-/-, LXRβ-/-, and LXRα/β-/- mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction.

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JO - Diabetes

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ER -

Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes

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