Related Experiment Video
Updated: Dec 5, 2025
Author Spotlight: Unraveling Vitamin A Transport Mechanisms — Linking Liver Receptors to Vision Health Through RBPR2 and RBP4 Interactions
Published on: October 4, 2024
Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved
Shyi-Jang Shin1, Chao-Hung Chen2, Wen-Chen Kuo3
1Grander Clinic, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Background:
Retinol-binding protein 4 (RBP4) is elevated and associated with inflammation in metabolic diseases. Disruption of the retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6) are found in diabetic kidneys.
Objectives:
We investigated whether the disruption of the retinol cascade induces RBP4 overproduction and if O-linked GlcNAc modification targets RBPR2 and contributes to the disruption of retinol cascades in diabetic livers.
Methods:
Western blot or immunohistochemistry for RBPR2, CRBP1, LRAT, RALDH, RARα, RARγ, RXRα, RBP4, GFAT, OGT, OGA and inflammatory markers, as well as ELISA for RBP4, were performed in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. Immunoprecipitation and dual fluorescence staining were used to explore O-GlcNAc-modified RBPR2 and RBP4 binding activity on RBPR2. Transfection of the CRBP1 gene was done to verify whether a disrupted retinol cascade induces RBP4 overproduction. OGT silencing was done to investigate the association of O-GlcNAcylation with the disruption of retinol cascade.
Results:
Disruption of retinol cascade, RBP4 overproduction, O-GlcNAcylation of RBPR2, decreased RBP4 binding activity on RBPR2 and inflammation were found in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. CRBP1 gene transfection reversed the suppression of the cellular retinol cascade and simultaneously attenuated the RBP4 overproduction and inflammation in high glucose-treated hepatocytes. The silencing of OGT reversed the disruption of the cellular retinol cascade, RBP4 overproduction and inflammation induced by high glucose in hepatocytes.
Conclusions:
This study indicates that the disruption of cellular retinol cascade is strongly associated with RBP4 overproduction and inflammation in diabetic livers. RBPR2 is one target for high glucose-mediated O-linked GlcNAc modification, which causes liver retinol dyshomeostasis.
Insights
Diabetic liver disease involves disrupted retinol cascades and increased RBP4. O-linked GlcNAc modification of RBPR2 contributes to this, leading to inflammation and retinol dyshomeostasis.
Area of Science:
- Biochemistry
- Metabolic Diseases
- Molecular Biology
Background:
- Retinol-binding protein 4 (RBP4) elevation is linked to inflammation in metabolic diseases.
- Diabetic kidneys show disrupted retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6).
Purpose of the Study:
- To investigate if retinol cascade disruption causes RBP4 overproduction.
- To determine if O-linked GlcNAc modification targets RBPR2 and disrupts retinol cascades in diabetic livers.
Main Methods:
- Western blot and immunohistochemistry were used to analyze key proteins (RBPR2, CRBP1, RBP4, etc.) and inflammatory markers in mouse models and hepatocytes.
- Immunoprecipitation and dual fluorescence staining assessed O-GlcNAc-modified RBPR2 and RBP4 binding.
- Gene transfection (CRBP1) and silencing (OGT) were employed to confirm causality.
Main Results:
- Diabetic livers and high glucose-treated hepatocytes exhibited retinol cascade disruption, RBP4 overproduction, RBPR2 O-GlcNAcylation, reduced RBP4 binding, and inflammation.
- CRBP1 transfection normalized the retinol cascade, reduced RBP4 overproduction, and attenuated inflammation.
- OGT silencing reversed high glucose-induced retinol cascade disruption, RBP4 overproduction, and inflammation.
Conclusions:
- Disruption of the cellular retinol cascade is closely linked to RBP4 overproduction and inflammation in diabetic livers.
- RBPR2 is a target of high glucose-mediated O-linked GlcNAc modification, leading to liver retinol dyshomeostasis.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:20Pathophysiology of Diabetes
Type 1 diabetes is characterized by autoimmune-mediated destruction of pancreatic β cells, with environmental factors potentially triggering this process in genetically susceptible individuals. Despite many not having a family history, certain genes increase susceptibility,...