Study of the mechanism by which HDAC3 regulates lipid synthesis in retinal ganglion cells by modulating SREBP-1c acetylation

BACKGROUND: Diabetic retinopathy (DR) is characterized by early retinal neurodegeneration, with its pathological mechanisms closely linked to lipid metabolism disorders. Although histone deacetylase 3 (HDAC3) regulates systemic energy homeostasis, its role in lipid toxicity within DR neurons remains unclear. This study aimed to investigate whether HDAC3 drives lipid toxicity in retinal neurons by regulating the acetylation level of sterol regulatory element-binding protein 1c (SREBP-1c). METHODS: Mouse retinal ganglion-like cells (661 W) were treated under high-glucose conditions with HDAC3 overexpression (HDAC3-OE), pharmacological HDAC3 inhibition (RGFP966), and SREBP-1c functional restoration. Western blotting analyzed HDAC3 protein expression and SREBP-1c acetylation levels in each group. Co-immunoprecipitation was used to assess the association between HDAC3 and SREBP-1c, whereas ChIP-qPCR was used to evaluate SREBP-1c and HDAC3 enrichment at lipogenic gene promoters. Direct effects on cellular lipids were assessed via lipid quantification (triglycerides/cholesterol) and Oil Red O staining. RESULTS: The significant upregulation of HDAC3 expression (p < 0.05) and the reduction of SREBP-1c acetylation levels (p < 0.05) were the results of HG. Co-immunoprecipitation demonstrated an association between HDAC3 and SREBP-1c, and acetylation-IP analysis showed that HDAC3 activity negatively regulated SREBP-1c acetylation. These changes were accompanied by increased SREBP-1c nuclear accumulation and enhanced binding to the Fasn and Acc1 promoters (p < 0.001). The acetylation of SREBP-1c was restored by HDAC3 inhibition, lipid accumulation was reduced (p < 0.01), and inflammatory responses were reduced (p < 0.05). However, SREBP-1c overexpression reversed these protective effects (p < 0.05). CONCLUSION: High glucose induces HDAC3-dependent reduction of SREBP-1c acetylation, which promotes SREBP-1c nuclear accumulation and activation of lipogenic gene transcription in retinal neuronal cells. The pathway targeted here is shown to reduce lipid toxicity and inflammatory responses, which suggests that HDAC3 inhibition may represent a potential therapeutic strategy for neurodegenerative processes in DR.