Restoring retinal polyunsaturated fatty acid balance and retina function by targeting ceramide in AdipoR1-deficient mice

• DOI: 10.1016/j.jbc.2024.107291
• Publication Date: 2024-04-16T09:51:43Z
• Authors: Dominik Lewandowski; Fangyuan Gao; Sanae Imanishi; Aleksander Tworak; Marco Bassetto; Zhiqian Dong; Antonio F.M. Pinto; Marcin Tabaka; Philip D. Kiser; Yoshikazu Imanishi; Dorota Skowronska...; Krzysztof Palczewski
• Keywords: Knockout; Fatty acid transport; PPARα signaling; adiponectin receptor 1; Retinal Pigment Epithelium; Ceramides; Retina; RPE deposits; Mice; Macular Degeneration; retinitis pigmentosa; lipid metabolism; Receptors; Omega-3 fatty acids; Bardet-Biedl syndrome; Animals; Omega-6 fatty acids; ceramide synthesis inhibition; Retinal degeneration; age-related macular degeneration; fatty acid oxidation; fatty acid transport; Unsaturated; ceramides; omega-3 fatty acids; Age-related macular degeneration; Fatty Acids; omega-6 fatty acids; Retinitis pigmentosa; Adiponectin receptor 1; Lipid metabolism; Fatty acid oxidation; retinal degeneration; Ceramide synthesis inhibition; Polyunsaturated fatty acids; Adiponectin; polyunsaturated fatty acids; Research Article

Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration (AMD). This study explores effects of AdipoR1 deficiency mice, revealing a striking decline ω3 polyunsaturated fatty acids (PUFA), an increase ω6 FAs, elevated ceramides retina. The impairs peroxisome proliferator-activated α (PPARα) signaling, which is crucial for FA metabolism, particularly affecting proteins transport oxidation retina retinal pigmented epithelium (RPE). Our lipidomic proteomic analyses indicate changes that could affect membrane composition viscosity through altered PUFA synthesis, suggesting potential influence on these properties. Furthermore, we noted reduction Bardet-Biedl syndrome (BBS) proteins, forming maintaining photoreceptor outer segments PUFA-enriched ciliary structures. Diminution BBS-proteins content combined our electron microscopic observations raises possibility might impair function. Treatment inhibitors ceramide synthesis led substantial elevation LC-PUFAs, alleviating improving These results serve as proof concept ceramide-targeted strategy treat retinopathies linked deficiency, including AMD.