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Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina.

Yu JY, Lyons TJ - J Clin Exp Ophthalmol (2013)

Bottom Line: Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids.In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells.This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

View Article: PubMed Central - PubMed

Affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.

ABSTRACT
Clinical epidemiological studies have revealed relatively weak, yet statistically significant, associations between dyslipidemia/dyslipoproteinemia and diabetic retinopathy (DR). Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids. To unify the apparent discrepancies, we hypothesize that plasma lipoproteins play an indirect but important role in DR, contingent on the integrity of the blood-retina-barrier (BRB). In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells. In this hypothesis, BRB leakage is the key, plasma lipoprotein concentrations mainly modulate its consequences, and fenofibrate has intra-retinal actions. This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

No MeSH data available.


Related in: MedlinePlus

A working hypothesis of modified lipoproteins in the pathogenesis of DR. The role of circulating lipoproteins in DR depends on the integrity of BRB. Normally, plasma LDL does not cause retinal damage, but plasma ox- LDL (mostly mildly modified) may contribute to the initial BRB impairment, together with many other metabolic factors that are commonly seen in diabetes. Once the BRB becomes leaky, even in a short period, LDL can extravasate, aggregate, and become progressively modified by oxidation and glycation in the extracellular milieu, resulting in generalized damages to all retinal cell types in proximity. Extravasation of lipoproteins is expected to gradually turn intermittent, transient BRB impairment into a prolonged, chronic pathological state. In this model, fenofibrate may attenuate retinopathy by modulating intra-retinal lipid processing and inflammation, with the efficacy unrelated to its systemic lipid-lowering effect. The retinal pathology caused by extravascular modified lipoproteins is largely isolated from the circulating lipids, consistent with the generally weak association between plasma lipids and DR in epidemiological studies.
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Figure 1: A working hypothesis of modified lipoproteins in the pathogenesis of DR. The role of circulating lipoproteins in DR depends on the integrity of BRB. Normally, plasma LDL does not cause retinal damage, but plasma ox- LDL (mostly mildly modified) may contribute to the initial BRB impairment, together with many other metabolic factors that are commonly seen in diabetes. Once the BRB becomes leaky, even in a short period, LDL can extravasate, aggregate, and become progressively modified by oxidation and glycation in the extracellular milieu, resulting in generalized damages to all retinal cell types in proximity. Extravasation of lipoproteins is expected to gradually turn intermittent, transient BRB impairment into a prolonged, chronic pathological state. In this model, fenofibrate may attenuate retinopathy by modulating intra-retinal lipid processing and inflammation, with the efficacy unrelated to its systemic lipid-lowering effect. The retinal pathology caused by extravascular modified lipoproteins is largely isolated from the circulating lipids, consistent with the generally weak association between plasma lipids and DR in epidemiological studies.

Mentions: To provide a working model that will connect the apparently disparate observations (i.e. relatively weak association data from epidemiological studies, robust efficacy of fenofibrate in clinical intervention studies, and extensive laboratory data showing deleterious effects of modified, but not native, lipoproteins on retinal cells (discussed below)), our evolved thinking is that plasma lipoproteins play a ‘hidden’, indirect role on DR, which is dependent on the breakdown of the blood-retina-barrier (BRB) (Figure 1). In normal retina with an intact BRB, plasma lipoproteins are largely irrelevant; however, their effects become operative after the BRB becomes deficient (as in diabetes), allowing extravasation of lipoproteins which then become modified (i.e. oxidized and/or glycated) in tissue, rendering them toxic towards nearby retinal cells. In this hypothesis, BRB leakage is the key, and plasma lipoprotein concentrations simply modulate its consequences. One limitation of the model is that the action of lipoproteins occurs only as a secondary effect of BRB leakage, not as the primary initiator. BRB impairment may be caused by many common, intermittent metabolic stresses that are present in diabetes, such as high and fluctuating glucose, free fatty acids, oxidative stress and osmotic stress [50-54], all of which may be acutely exacerbated during episodes of ketoacidosis. Extravasation of lipoproteins, we suggest, can gradually turn a transitory BRB impairment into prolonged, chronic pathology. Also, because of their cytotoxic effects on retinal capillary cells, higher levels of ox-LDL in circulation may pose a direct noxious effect on the BRB [55-57], contributing to the initiation of damage. Overall, the role of ox-LDL in DR is essentially analogous to that in atherosclerosis, in which elevated plasma levels of LDL and modified LDL are associated with cardiovascular disease, where the modification of LDL and its harmful effects occur primarily in the arterial intima, not in plasma. In the retina, certain unique features are operative: retinal lipoprotein exudates appear in the perivascular extracellular space adjacent to the neural retina, due to the small size of retinal capillaries [49], and may thus produce generalized retinal neurovascular injuries [58]. Also, because LDL is normally excluded completely from the retina, the ‘fold increase’ once BRB leakage occurs is much greater in the retina than in the arterial intima.


Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina.

Yu JY, Lyons TJ - J Clin Exp Ophthalmol (2013)

A working hypothesis of modified lipoproteins in the pathogenesis of DR. The role of circulating lipoproteins in DR depends on the integrity of BRB. Normally, plasma LDL does not cause retinal damage, but plasma ox- LDL (mostly mildly modified) may contribute to the initial BRB impairment, together with many other metabolic factors that are commonly seen in diabetes. Once the BRB becomes leaky, even in a short period, LDL can extravasate, aggregate, and become progressively modified by oxidation and glycation in the extracellular milieu, resulting in generalized damages to all retinal cell types in proximity. Extravasation of lipoproteins is expected to gradually turn intermittent, transient BRB impairment into a prolonged, chronic pathological state. In this model, fenofibrate may attenuate retinopathy by modulating intra-retinal lipid processing and inflammation, with the efficacy unrelated to its systemic lipid-lowering effect. The retinal pathology caused by extravascular modified lipoproteins is largely isolated from the circulating lipids, consistent with the generally weak association between plasma lipids and DR in epidemiological studies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109058&req=5

Figure 1: A working hypothesis of modified lipoproteins in the pathogenesis of DR. The role of circulating lipoproteins in DR depends on the integrity of BRB. Normally, plasma LDL does not cause retinal damage, but plasma ox- LDL (mostly mildly modified) may contribute to the initial BRB impairment, together with many other metabolic factors that are commonly seen in diabetes. Once the BRB becomes leaky, even in a short period, LDL can extravasate, aggregate, and become progressively modified by oxidation and glycation in the extracellular milieu, resulting in generalized damages to all retinal cell types in proximity. Extravasation of lipoproteins is expected to gradually turn intermittent, transient BRB impairment into a prolonged, chronic pathological state. In this model, fenofibrate may attenuate retinopathy by modulating intra-retinal lipid processing and inflammation, with the efficacy unrelated to its systemic lipid-lowering effect. The retinal pathology caused by extravascular modified lipoproteins is largely isolated from the circulating lipids, consistent with the generally weak association between plasma lipids and DR in epidemiological studies.
Mentions: To provide a working model that will connect the apparently disparate observations (i.e. relatively weak association data from epidemiological studies, robust efficacy of fenofibrate in clinical intervention studies, and extensive laboratory data showing deleterious effects of modified, but not native, lipoproteins on retinal cells (discussed below)), our evolved thinking is that plasma lipoproteins play a ‘hidden’, indirect role on DR, which is dependent on the breakdown of the blood-retina-barrier (BRB) (Figure 1). In normal retina with an intact BRB, plasma lipoproteins are largely irrelevant; however, their effects become operative after the BRB becomes deficient (as in diabetes), allowing extravasation of lipoproteins which then become modified (i.e. oxidized and/or glycated) in tissue, rendering them toxic towards nearby retinal cells. In this hypothesis, BRB leakage is the key, and plasma lipoprotein concentrations simply modulate its consequences. One limitation of the model is that the action of lipoproteins occurs only as a secondary effect of BRB leakage, not as the primary initiator. BRB impairment may be caused by many common, intermittent metabolic stresses that are present in diabetes, such as high and fluctuating glucose, free fatty acids, oxidative stress and osmotic stress [50-54], all of which may be acutely exacerbated during episodes of ketoacidosis. Extravasation of lipoproteins, we suggest, can gradually turn a transitory BRB impairment into prolonged, chronic pathology. Also, because of their cytotoxic effects on retinal capillary cells, higher levels of ox-LDL in circulation may pose a direct noxious effect on the BRB [55-57], contributing to the initiation of damage. Overall, the role of ox-LDL in DR is essentially analogous to that in atherosclerosis, in which elevated plasma levels of LDL and modified LDL are associated with cardiovascular disease, where the modification of LDL and its harmful effects occur primarily in the arterial intima, not in plasma. In the retina, certain unique features are operative: retinal lipoprotein exudates appear in the perivascular extracellular space adjacent to the neural retina, due to the small size of retinal capillaries [49], and may thus produce generalized retinal neurovascular injuries [58]. Also, because LDL is normally excluded completely from the retina, the ‘fold increase’ once BRB leakage occurs is much greater in the retina than in the arterial intima.

Bottom Line: Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids.In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells.This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

View Article: PubMed Central - PubMed

Affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.

ABSTRACT
Clinical epidemiological studies have revealed relatively weak, yet statistically significant, associations between dyslipidemia/dyslipoproteinemia and diabetic retinopathy (DR). Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids. To unify the apparent discrepancies, we hypothesize that plasma lipoproteins play an indirect but important role in DR, contingent on the integrity of the blood-retina-barrier (BRB). In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells. In this hypothesis, BRB leakage is the key, plasma lipoprotein concentrations mainly modulate its consequences, and fenofibrate has intra-retinal actions. This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

No MeSH data available.


Related in: MedlinePlus