CD36 plays an important role in the clearance of oxLDL and associated age-dependent sub-retinal deposits

Picard, Émilie; Houssier, Marianne; Bujold, Kim; Sapieha, Przemysław; Lubell, William D.; Dorfman, Allison; Racine, Julie; Hardy, Pierre; Febbraio, Maria; Lachapelle, Pierre; Ong, Huy; Sennlaub, Florian; Chemtob, Sylvain

doi:10.18632/aging.100218

Cited by 71 publications

(71 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, oxLDL has been shown to stimulate extracellular matrix production. Because both LDL and oxLDL may contribute to the pathogenesis of AMD (29,30), we examined the degree to which LDL and oxLDL regulate RPE production and secretion of collagen IV, an extracellular matrix molecule found in sub-RPE deposits, through AhR (Fig. 8 D and E).…”

Section: Amd-like Rpe and Choroidal Pathology In Ahrmentioning

confidence: 99%

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Hu¹,

Herrmann²,

Bednar³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR −/− mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR −/− mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.retinal pigment epithelium | retinal disease | toxin metabolism | oxidized low density lipoprotein A ge-related macular degeneration (AMD) is the leading cause of vision loss in individuals over the age of 55 y in the Western world (1). It is a complex and heterogeneous disease, multifactorial with genetic, systemic health, and environmental factors regulating its initiation and progression (2, 3). Phenotypically, eyes with the dry clinical subtype are characterized by accumulation of focal and diffuse extracellular lipid protein-rich deposits below the retinal pigment epithelial cells (sub-RPE in 85-87% of cases) and/or within Bruch's membrane. These deposits include drusen, basal laminar, and basal linear deposits (4, 5) and are associated with RPE dysfunction, apoptosis, and ultimately degeneration. The latter of which, RPE atrophy and degeneration, is seen in an advanced form of dry AMD called geographic atrophy. Currently, there are no treatment options available for these patients. Despite advances in our understanding of the composition of sub-RPE deposits (6-8), the critical molecular events and signaling pathways leading to progressive RPE dysfunction and extracellular deposit biogenesis are still unknown.

show abstract

Section: Amd-like Rpe and Choroidal Pathology In Ahrmentioning

confidence: 99%

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Hu¹,

Herrmann²,

Bednar³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

show abstract

“…While a number of sophisticated in vitro assays have been developed for assessing endothelial barrier function (Wegener & Seebach, 2014), we sought to assess a potentially more physiologically relevant model by analyzing mice with a conditional endothelial deletion of ATG7 (Torisu et al, 2013). We took advantage of the rich vascular plexus in the eye and the previously described transport of lipids from the choroidal blood vessels to the retinal pigment epithelium (RPE) (Picard et al, 2010). To assess whether the acute handling of modified lipids depends on intact endothelial autophagy, we injected control mice (WT/WT; VE-Cadherin Cre) or Atg7 endo mice (fl/fl;VE-Cadherin Cre) mice with fluorescently labeled OxLDL (dil-OxLDL).We next analyzed the retinas of mice 24 and 48 h after OxLDL injection by confocal microscopy.…”

mentioning

confidence: 99%

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

et al. 2015

View full text Add to dashboard Cite

SummaryThe physiological role of autophagic flux within the vascular endothelial layer remains poorly understood. Here, we show that in primary endothelial cells, oxidized and native LDL stimulates autophagosome formation. Moreover, by both confocal and electron microscopy, excess native or modified LDL appears to be engulfed within autophagic structures. Transient knockdown of the essential autophagy gene ATG7 resulted in higher levels of intracellular 125 I-LDL and oxidized LDL (OxLDL) accumulation, suggesting that in endothelial cells, autophagy may represent an important mechanism to regulate excess, exogenous lipids. The physiological importance of these observations was assessed using mice containing a conditional deletion of ATG7 within the endothelium. Following acute intravenous infusion of fluorescently labeled OxLDL, mice lacking endothelial expression of ATG7 demonstrated prolonged retention of OxLDL within the retinal pigment epithelium (RPE) and choroidal endothelium of the eye. In a chronic model of lipid excess, we analyzed atherosclerotic burden in ApoE À/À mice with or without endothelial autophagic flux. The absence of endothelial autophagy markedly increased atherosclerotic burden. Thus, in both an acute and chronic in vivo model, endothelial autophagy appears critically important in limiting lipid accumulation within the vessel wall. As such, strategies that stimulate autophagy, or prevent the agedependent decline in autophagic flux, might be particularly beneficial in treating atherosclerotic vascular disease.Key words: autophagy; lipids; atherosclerosis; mouse.Cardiovascular disease, driven in part by the accumulation of modified lipids within the vessel wall, represents the leading cause of death in developed nations (Go et al., 2013). Considerable attention and study has been directed at the molecular consequences following the subendothelial deposition of lipids. These consequences include the recruitment of inflammatory cells and the subsequent engulfment of this deposited subendothelial lipid by resident macrophages (Chinetti-Gbaguidi et al., 2014;Randolph, 2014). In contrast, relatively little is known regarding the steps proximal to lipid deposition and what regulatory role, if any, the endothelium might play in this process. While evidence is limited for the case of the endothelium, in other cell types it appears that autophagy may play a critical role in maintaining overall lipid homeostasis. For instance, mice bearing ATG5-deficient macrophages appear to exhibit increased plaque formation when bred with pro-atherogenic mouse strains (Liao et al., 2012;Razani et al., 2012). While the basis for this increased plaque burden is undoubtedly complex, evidence suggests that macrophage-specific ATG5 deletion results in impaired lipophagy (Sergin & Razani, 2014). Lipophagy refers to the specific degradation of lipids by the autophagic machinery. This concept was perhaps first described in the liver where genetic disruption of macroautophagy led to the accumulation of lipid droplets (Singh...

show abstract

“…We also observed that the level of serum ox-LDL in premature CHD patients was higher than in controls. The main way to eliminate ox-LDL is phagocytosis of macrophages by SR, whose main member is CD36 (Park et al, 2012;Picard et al, 2010). So, the polymorphism of the CD36 gene could influence the level of ox-LDL.…”

Section: Discussionmentioning

confidence: 99%

Association between rs1049673 polymorphism in CD36 and premature coronary heart disease

Che¹,

Shao²,

Li³

2014

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Risk factors for premature coronary heart disease in China can be multiple; we investigated Chinese Han patients with premature coronary heart disease and a possible association with CD36 polymorphism at rs1049673, rs7755, and rs321159 sites. Outpatients were recruited according to chest X-ray coronary arteriography results; they were divided into two groups: early coronary artery lesions (premature coronary heart disease group, test group) and a control group. Coronary arteriography and laboratory blood examinations were conducted to analyze risk factors for coronary heart disease and CD36 polymorphisms. Seventy nine test and 56 control group patients were recruited. Compared with the control, the test groups had a significantly higher proportion of male patients, smoking, diabetes and metabolic syndromes, significantly higher levels of TG, LDL-C, ox-LDL, WBC, UA, FBG, and significantly lower levels of HDL-C. For rs1049673, rs7755, and rs321159 sites, patients with premature coronary heart disease have family genetic predisposition at high LDL-C level with GA, AA, and TT genotypes. Unconditional logistic regression analysis showed that gender, diabetes, high TG, LDL-C level and C carriers 7709 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (3): 7708-7717 (2014) Premature coronary heart disease predisposition analysis of rs1049673 significantly affected risk for premature coronary heart disease.

show abstract

CD36 plays an important role in the clearance of oxLDL and associated age-dependent sub-retinal deposits

Cited by 71 publications

References 42 publications

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

Association between rs1049673 polymorphism in CD36 and premature coronary heart disease

Contact Info

Product

Resources

About