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

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.

Beneficial Effects of Berberine on Oxidized LDL-Induced Cytotoxicity to Human Retinal Müller Cells

“…1 B). To evaluate the effect of berberine on LDL-cell interactions, we employed N-LDL and HOG-LDL at 200 mg/L, a concentration we consider to be pathophysiologically relevant in DR. 8 Native-LDL did not affect cell viability, while HOG-LDL reduced it by approximately 50% ( Fig. 1 B).…”

“…Previously we have demonstrated that in people with diabetes, LDL becomes extravasated through leaking BRBs, and subsequently modified by oxidation and glycation even in the ‘preclinical' stages of DR. 4 – 7 Therefore, we have postulated that in addition to hyperglycemia, extravasation, and modification of plasma lipoproteins, with resultant cytotoxicity, are important drivers of DR. 8 We found that among other adverse effects, modified LDL induces death in several types of human retinal cells. 5 , 6 , 9 Specifically, Müller cell culture studies revealed that modified LDL causes oxidative and endoplasmic reticulum (ER) stresses, and apoptotic death, but the detailed underlying mechanisms of cellular injury are not yet fully understood.…”

Risk factors for development and progression of diabetic retinopathy in Dutch patients with type 1 diabetes mellitus

“…The potential mechanism of action of the association between lipids and DR is also unclear. It has been hypothesized that lipoproteins leak through the disrupted blood–retinal barrier and have a cytotoxic effect on retinal cells (Yu & Lyons 2013). Others hypothesized that lipoproteins interact with the activation of protein kinase C and advanced glycation end product formation – two pathways involved in DR pathophysiology (Chang & Wu 2013).…”

MicroRNA-126 contributes to Niaspan treatment induced vascular restoration after diabetic retinopathy

“…HDL also stimulates production of endothelial nitric oxide and induces anti-apoptotic, anti-inflammatory and anti-thrombotic properties20. Clinical epidemiological studies have demonstrated that dyslipidemia/dyslipoproteinemia is significantly correlated with DR patients21. Serum Apo-B and Apo-B/Apo-A ratio were the most significant metabolic risk factors for PDR22.…”