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

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-Krawczyk; Krzysztof Palczewski

doi:10.1016/j.jbc.2024.107291

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

J Biol Chem. 2024 Apr 16;300(5):107291. doi: 10.1016/j.jbc.2024.107291. Online ahead of print.

Affiliations

¹ Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, California, USA. Electronic address: lewandod@hs.uci.edu.
² Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, California, USA.
³ Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ Department of Physiology and Biophysics, University of California, Irvine, California, USA.
⁵ Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA.
⁶ International Centre for Translational Eye Research, Warsaw, Poland; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland.
⁷ Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, California, USA; Department of Physiology and Biophysics, University of California, Irvine, California, USA; Department of Clinical Pharmacy Practice, University of California, Irvine, California, USA; Research Service, Veterans Affairs Long Beach Healthcare System, Long Beach, California, USA.
⁸ Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, California, USA; Department of Physiology and Biophysics, University of California, Irvine, California, USA.
⁹ Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, California, USA; Department of Physiology and Biophysics, University of California, Irvine, California, USA; Department of Chemistry, and Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA. Electronic address: kpalczew@uci.edu.

PMID: 38636661
DOI: 10.1016/j.jbc.2024.107291

Abstract

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

Keywords: Bardet-Biedl syndrome; PPARα signaling; RPE deposits; adiponectin receptor 1; age-related macular degeneration; ceramide synthesis inhibition; ceramides; fatty acid oxidation; fatty acid transport; lipid metabolism; omega-3 fatty acids; omega-6 fatty acids; polyunsaturated fatty acids; retinal degeneration; retinitis pigmentosa.

Grants and funding

I01 BX004939/BX/BLRD VA/United States