# The Liver–Eye Axis of Dietary Vitamin A Homeostasis: A Review of Mechanisms, Receptors, and Visual Outcomes

## TL;DR

This paper reviews how vitamin A is stored in the liver and transported to the eye, focusing on a protein called RBPR2 and its role in maintaining vision and retinal health.

## Contribution

The paper highlights the novel role of RBPR2 in regulating vitamin A transport between the liver and eye, and its potential as a therapeutic target.

## Key findings

- Loss of RBPR2 in mice leads to impaired vitamin A uptake in the liver and reduced retinoid content in the eye, causing visual dysfunction.
- Dietary vitamin A deficiency amplifies the negative effects of RBPR2 deficiency, worsening retinal health.
- Modulating RBPR2 expression in mouse models of Stargardt disease reduces retinal cell degeneration and lipofuscin accumulation.

## Abstract

Background: Vitamin A is an essential micronutrient critical for vision, immune function, cellular differentiation, and metabolic homeostasis. The liver serves as the primary site of vitamin A storage and systemic distribution, delivering all-trans-retinol (ROL) to peripheral tissues, including the retina, via retinol-binding protein 4 (RBP4). Tight regulation of retinoid delivery to peripheral tissues is crucial for metabolic function and photoreceptor integrity. Objectives: This review provides a current understanding of intestinal absorption, hepatic storage, systemic transport, and ocular utilization of vitamin A, with a focus on the role of retinol-binding protein 4 receptor 2 (RBPR2) in mediating liver–eye communication. Results: Studies using Rbpr2 knockout mice show that loss of RBPR2 impairs hepatic ROL-bound RBP4 uptake and retinyl ester concentrations, alters circulating holo-RBP4 levels, and reduces ocular retinoid content, leading to visual dysfunction and photoreceptor structural abnormalities. These effects are amplified under dietary vitamin A-deficient conditions, highlighting its unique sensitivity to tightly regulated serum RBP4-ROL transport. In mouse models of Stargardt disease, dietary modulation of RBPR2 mRNA expression and serum RBP4-ROL levels protects against lipofuscin accumulation and attenuates retinal cell degeneration, suggesting translational relevance. Conclusions: This review article explores the liver–eye axis by focusing on the regulation of retinoid homeostasis in the liver and other systemic organs through the non-ocular RBP4 receptor protein, RBPR2, and how RBPR2 expression may influence liver and serum retinoid homeostasis, which can impact visual function. Disruption of RBPR2 markedly compromises systemic and retinal retinoid supply, emphasizing its potential as a therapeutic target for metabolic and retinal disorders.