Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium
Like other neurons, retinal cells utilize autophagic pathways to maintain cell homeostasis. The mammalian retina relies on heterophagy and selective autophagy to efficiently degrade and metabolize ingested lipids with disruption in autophagy associated degradation contributing to age related retinal...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2018-10-01
|
Series: | Frontiers in Cellular Neuroscience |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2018.00351/full |
id |
doaj-eb1e6a537f84441ebe0344c9f1b55781 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anuradha Dhingra Brent A. Bell Neal S. Peachey Neal S. Peachey Neal S. Peachey Lauren L. Daniele Juan Reyes-Reveles Rachel C. Sharp Bokkyoo Jun Nicolas G. Bazan Janet R. Sparrow Hye Jin Kim Nancy J. Philp Kathleen Boesze-Battaglia |
spellingShingle |
Anuradha Dhingra Brent A. Bell Neal S. Peachey Neal S. Peachey Neal S. Peachey Lauren L. Daniele Juan Reyes-Reveles Rachel C. Sharp Bokkyoo Jun Nicolas G. Bazan Janet R. Sparrow Hye Jin Kim Nancy J. Philp Kathleen Boesze-Battaglia Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium Frontiers in Cellular Neuroscience LC3-associated phagocytosis (LAP) retinal pigment epithelium lipid metabolism oxidative stress mouse model |
author_facet |
Anuradha Dhingra Brent A. Bell Neal S. Peachey Neal S. Peachey Neal S. Peachey Lauren L. Daniele Juan Reyes-Reveles Rachel C. Sharp Bokkyoo Jun Nicolas G. Bazan Janet R. Sparrow Hye Jin Kim Nancy J. Philp Kathleen Boesze-Battaglia |
author_sort |
Anuradha Dhingra |
title |
Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium |
title_short |
Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium |
title_full |
Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium |
title_fullStr |
Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium |
title_full_unstemmed |
Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium |
title_sort |
microtubule-associated protein 1 light chain 3b, (lc3b) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular Neuroscience |
issn |
1662-5102 |
publishDate |
2018-10-01 |
description |
Like other neurons, retinal cells utilize autophagic pathways to maintain cell homeostasis. The mammalian retina relies on heterophagy and selective autophagy to efficiently degrade and metabolize ingested lipids with disruption in autophagy associated degradation contributing to age related retinal disorders. The retinal pigment epithelium (RPE) supports photoreceptor cell renewal by daily phagocytosis of shed photoreceptor outer segments (OS). The daily ingestion of these lipid-rich OS imposes a constant degradative burden on these terminally differentiated cells. These cells rely on Microtubule-Associated Protein 1 Light Chain 3 (LC3) family of proteins for phagocytic clearance of the ingested OS. The LC3 family comprises of three highly homologous members, MAP1LC3A (LC3A), MAP1LC3B (LC3B), and MAP1LC3C (LC3C). The purpose of this study was to determine whether the LC3B isoform plays a specific role in maintaining RPE lipid homeostasis. We examined the RPE and retina of the LC3B-/- mouse as a function of age using in vivo ocular imaging and electroretinography coupled with ex vivo, lipidomic analyses of lipid mediators, assessment of bisretinoids as well as imaging of lipid aggregates. Deletion of LC3B resulted in defects within the RPE including increased phagosome accumulation, decreased fatty acid oxidation and a subsequent increase in RPE and sub-RPE lipid deposits. Age-dependent RPE changes included elevated levels of oxidized cholesterol, deposition of 4-HNE lipid peroxidation products, bisretinoid lipofuscin accumulation, and subretinal migration of microglia, collectively likely contributing to loss of retinal function. These observations are consistent with a critical role for LC3B-dependent processes in the maintenance of normal lipid homeostasis in the aging RPE, and suggest that LC3 isoform specific disruption in autophagic processes contribute to AMD-like pathogenesis. |
topic |
LC3-associated phagocytosis (LAP) retinal pigment epithelium lipid metabolism oxidative stress mouse model |
url |
https://www.frontiersin.org/article/10.3389/fncel.2018.00351/full |
work_keys_str_mv |
AT anuradhadhingra microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT brentabell microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT nealspeachey microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT nealspeachey microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT nealspeachey microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT laurenldaniele microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT juanreyesreveles microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT rachelcsharp microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT bokkyoojun microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT nicolasgbazan microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT janetrsparrow microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT hyejinkim microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT nancyjphilp microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium AT kathleenboeszebattaglia microtubuleassociatedprotein1lightchain3blc3bisnecessarytomaintainlipidmediatedhomeostasisintheretinalpigmentepithelium |
_version_ |
1725516323539124224 |
spelling |
doaj-eb1e6a537f84441ebe0344c9f1b557812020-11-24T23:38:40ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-10-011210.3389/fncel.2018.00351386482Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment EpitheliumAnuradha Dhingra0Brent A. Bell1Neal S. Peachey2Neal S. Peachey3Neal S. Peachey4Lauren L. Daniele5Juan Reyes-Reveles6Rachel C. Sharp7Bokkyoo Jun8Nicolas G. Bazan9Janet R. Sparrow10Hye Jin Kim11Nancy J. Philp12Kathleen Boesze-Battaglia13Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesScheie Eye Institute, University of Pennsylvania, Philadelphia, PA, United StatesCole Eye Institute, Cleveland Clinic, Cleveland, OH, United StatesLouis Stokes Cleveland VA Medical Center, Cleveland, OH, United StatesDepartment of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesNeuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, United StatesNeuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, United StatesDepartment of Ophthalmology, Columbia University Medical Center, New York, NY, United StatesDepartment of Ophthalmology, Columbia University Medical Center, New York, NY, United StatesDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United StatesDepartment of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesLike other neurons, retinal cells utilize autophagic pathways to maintain cell homeostasis. The mammalian retina relies on heterophagy and selective autophagy to efficiently degrade and metabolize ingested lipids with disruption in autophagy associated degradation contributing to age related retinal disorders. The retinal pigment epithelium (RPE) supports photoreceptor cell renewal by daily phagocytosis of shed photoreceptor outer segments (OS). The daily ingestion of these lipid-rich OS imposes a constant degradative burden on these terminally differentiated cells. These cells rely on Microtubule-Associated Protein 1 Light Chain 3 (LC3) family of proteins for phagocytic clearance of the ingested OS. The LC3 family comprises of three highly homologous members, MAP1LC3A (LC3A), MAP1LC3B (LC3B), and MAP1LC3C (LC3C). The purpose of this study was to determine whether the LC3B isoform plays a specific role in maintaining RPE lipid homeostasis. We examined the RPE and retina of the LC3B-/- mouse as a function of age using in vivo ocular imaging and electroretinography coupled with ex vivo, lipidomic analyses of lipid mediators, assessment of bisretinoids as well as imaging of lipid aggregates. Deletion of LC3B resulted in defects within the RPE including increased phagosome accumulation, decreased fatty acid oxidation and a subsequent increase in RPE and sub-RPE lipid deposits. Age-dependent RPE changes included elevated levels of oxidized cholesterol, deposition of 4-HNE lipid peroxidation products, bisretinoid lipofuscin accumulation, and subretinal migration of microglia, collectively likely contributing to loss of retinal function. These observations are consistent with a critical role for LC3B-dependent processes in the maintenance of normal lipid homeostasis in the aging RPE, and suggest that LC3 isoform specific disruption in autophagic processes contribute to AMD-like pathogenesis.https://www.frontiersin.org/article/10.3389/fncel.2018.00351/fullLC3-associated phagocytosis (LAP)retinal pigment epitheliumlipid metabolismoxidative stressmouse model |