Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival

Abstract

The identification of pathways necessary for photoreceptor and retinal pigment epithelium (RPE) function is critical to uncover blindness therapies. Here we report the discovery of adiponectin receptor 1 (AdipoR1) as a regulator of these cells’ functions. Docosahexaenoic acid (DHA) is avidly retained in photoreceptors, while mechanisms controlling DHA uptake and retention are unknown. Thus, we demonstrate that AdipoR1 ablation results in DHA reduction. In situ hybridization reveals photoreceptor and RPE cell AdipoR1 expression, blunted in AdipoR1−/− mice. We also find decreased photoreceptor-specific phosphatiydylcholine containing very long chain polyunsaturated fatty acids and severely-attenuated electroretinograms. These changes precede progressive photoreceptor degeneration in AdipoR1−/− mice. RPE-rich eyecup cultures from AdipoR1−/− reveal impaired DHA uptake. AdipoR1 overexpression in RPE cells enhances DHA uptake, whereas AdipoR1 silencing has the opposite effect. These results establish AdipoR1 as a regulatory switch of DHA uptake, retention, conservation, and elongation in photoreceptors and RPE, thus preserving photoreceptor cell integrity.

Associations of human retinal very long-chain polyunsaturated fatty acids with dietary lipid biomarkers

“…We are therefore uncertain whether the significant associations of systemic lipid status with retinal VLCPUFAs in controls versus the nonsignifi cant associations in AMD subjects seen in Table 5 are simply refl ections of serum biomarker variability or if there are true differences in retina lipid uptake and metabolism between normal and AMD eyes. We did explore the possibility that variants in ELOVL4 (the key enzyme in VLC-PUFA synthesis) ( 20 ) or AdipoR1 (a regulator of VLC-PUFA synthesis associated with AMD risk) ( 38 ) could explain the difference between AMD and control eyes, but we found no evidence for their involvement ( Table 1 ). In agreement with our results, others could not attain a statistically signifi cant correlation between ELOVL4 gene and macular degeneration ( 28,42 ).…”

“…Part of the problem lies with the challenges of linking dietary lipid consumption patterns with actual levels in the tissue of interest, the human retina. Dietary surveys are imprecise DNA was also available for these phase II subjects, and we examined whether variants in ELOVL4 and AdipoR1 [a regulator of retinal VLC-PUFA levels ( 38 )] have any infl uence on AMD risk or lipid profi les in this cohort, but we found no signifi cant relationships, nor did we fi nd any statistically signifi cant infl uences for AMD grade ( Table 1 ; all P values for comparisons were >0.05).…”

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium

“…AdipoR1 and AdipoR2 are involved in regulating glucose levels and fatty acid breakdown (38). AdipoR1 acts as a regulatory switch of DHA uptake, retention, and conservation/ elongation in photoreceptors and the RPE (39). AdipoR1 also is predicted to contain seven transmembrane domains, but it is structurally and functionally distinct from G protein-coupled receptors (40).…”

Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats

“…This, together with our recent finding that Cav3 is disrupted (13) and STAT3 inactivated (9), which deranged eNOS signaling in diabetic myocardium with concomitantly reduced APN (9), indicates that APN signaling (e.g., AdipoR1/Cav3) is impaired in diabetes. Although AdipoR1 (14,15) and STAT3 (16) have both been shown to be important procell survival factors in multiple cells, their potential interplay in affecting postischemic cell survival in general and specifically in affecting the myocardial responsiveness to IPo cardioprotection in diabetes is unknown. We hypothesized that the impairment of cardiac APN signaling is responsible for the inactivation of STAT3 in diabetes that disables the ability of the diabetic heart to respond to IPo and that an intact or adequate AdipoR1/Cav3 interaction is critical for IPo to activate STAT3 via APN.…”