Fatty Acid-Binding Protein 4-Mediated Regulation Is Pivotally Involved in Retinal Pathophysiology: A Review.

Fatty acid-binding proteins (FABPs), a family of lipid chaperone molecules that are involved in intracellular lipid transportation to specific cellular compartments, stimulate lipid-associated responses such as biological signaling, membrane synthesis, transcriptional regulation, and lipid synthesis. Previous studies have shown that FABP4, a member of this family of proteins that are expressed in adipocytes and macrophages, plays pivotal roles in the pathogenesis of various cardiovascular and metabolic diseases, including diabetes mellitus (DM) and hypertension (HT). Since significant increases in the serum levels of FABP4 were detected in those patients, FABP4 has been identified as a crucial biomarker for these systemic diseases. In addition, in the field of ophthalmology, our group found that intraocular levels of FABP4 (ioFABP4) and free fatty acids (ioFFA) were substantially elevated in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO), for which DM and HT are also recognized as significant risk factors. Recent studies have also revealed that ioFABP4 plays important roles in both retinal physiology and pathogenesis, and the results of these studies have suggested potential molecular targets for retinal diseases that might lead to future new therapeutic strategies.

Fatty acid metabolism is involved in both retinal physiology and the pathology of retinal vascular diseases.

To study the pathophysiological roles of the fatty acid-binding proteins (FABPs) within the retina, we performed; (1) immunolabeling of human retinas, wild type (WT) rat and mouse retinas, rat models for diabetic retinopathy (DR) and retinitis pigmentosa (RP) with anti-FABP3, FABP4, FABP5, FABP7, FABP8 and FABP12, (2) electroretinogram (ERG) measurements of WT and FABP4-deficient (Fabp4-/-) mice, (3) ELISA or gas chromatography measurements of plasma (P-) and vitreous (V-) levels of FABP4 and vascular endothelial growth factor A (VEGFA), and fatty acids (FAs) from patients with retinal vascular disease (RVD) including proliferative DR (PDR, n = 30) and retinal vein occlusion (RVO, n = 18) and non-RVD (n = 18). Within the human retina, diverse expressions of FABP3, FABP4, FABP7 and FABP8 were identified. In contrast, positive immunoreactivities toward only FABP4 and FABP12 were detected in the cases of rat and mouse retinas, and interestingly, the FABP4 labeling patterns for the WT, DR and RP rat retinas were different. The ERG amplitudes of Fabp4-/- mice were enhanced compared with those of WT mice. The concentrations of V-FABP4, V-VEGFA and total FAs were significantly higher in RVD patients than in non-PDR patients (P < 0.05). The V-FAs levels of each were significantly and positively correlated with V-FABP4 and V-VEGFA, although no significant correlation between vitreous (V-) and plasma (P-) FABP4, VEGFA and FAs were detected. The current study reveals that V-FAs appear to have significant roles in both retinal physiology as well as the pathogenesis of RVD with FABP4, which is commonly expressed within the retina in most species.

Fatty Acid-Binding Proteins 4 and 5 Are Involved in the Pathogenesis of Retinal Vascular Diseases in Different Manners.

This study reports on the pathological significance of the vitreous fatty acid-binding protein (Vt-FABP) 4 and 5, and vascular endothelial growth factor A (Vt-VEGFA) in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Subjects with PDR (n = 20), RVO (n = 10), and controls (epiretinal membrane, n = 18) who had undergone vitrectomies were enrolled in this study. The levels of Vt-FABP4, Vt-FABP5, and Vt-VEGFA were evaluated by enzyme-linked immunosorbent assays (ELISA). Retinal circulation levels were measured by a laser-speckle flow analyzer (LSFA) and other relevant data were collected. The Vt-FABP5 levels were significantly (p < 0.05) elevated in patients with RVDs compared to control patients. This elevation was more evident in patients with RVO than with PDR. Log Vt-FABP5 was significantly correlated negatively or positively with all the LSFA retinal circulation indexes or Log triglycerides (r = 0.31, p = 0.031), respectively. However, the elevations in the Vt-FABP4 and Vt-VEGFA levels were more evident in the PDR group (p < 0.05) and these factors were correlated positively with Log fasting glucose and negatively with some of the LSFA retinal circulation indexes. Multivariable regression analyses indicated that the LSFA blood flows of the optic disc at baseline was an independent effector with Log Vt-FABP5 other than several possible factors including age, gender, Log triglycerides, Log Vt-FABP4 and Log Vt-VEGFA. These current findings suggest that Vt-FABP5 is involved in the pathogenesis of RVD in a manner that is different from that for Vt-FABP4 and Vt-VEGFA, presumably by regulating retinal circulation.