Targeting of MiR-33 Ameliorates Phenotypes Linked to Age-related Macular Degeneration

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2021 Mar 21

PMID 33744470

Citations 10

Authors

Gopalan Gnanaguru

Alexandre Wagschal

Justin Oh

Kahira L Saez-Torres

Tong Li

Ryan E Temel

Mark E Kleinman

Anders M Naar

Patricia A DAmore

Affiliations

Soon will be listed here.

Abstract

Abnormal cholesterol/lipid homeostasis is linked to neurodegenerative conditions such as age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. The most prevalent form, termed "dry" AMD, is characterized by pathological cholesterol accumulation beneath the retinal pigment epithelial (RPE) cell layer and inflammation-linked degeneration in the retina. We show here that the cholesterol-regulating microRNA miR-33 was elevated in the RPE of aging mice. Expression of the miR-33 target ATP-binding cassette transporter (ABCA1), a cholesterol efflux pump genetically linked to AMD, declined reciprocally in the RPE with age. In accord, miR-33 modulated ABCA1 expression and cholesterol efflux in human RPE cells. Subcutaneous delivery of miR-33 antisense oligonucleotides (ASO) to aging mice and non-human primates fed a Western-type high fat/cholesterol diet resulted in increased ABCA1 expression, decreased cholesterol accumulation, and reduced immune cell infiltration in the RPE cell layer, accompanied by decreased pathological changes to RPE morphology. These findings suggest that miR-33 targeting may decrease cholesterol deposition and ameliorate AMD initiation and progression.

Citing Articles

Update on Clinical Trial Endpoints in Gene Therapy Trials for Inherited Retinal Diseases.

Igoe J, Lam B, Gregori N J Clin Med. 2024; 13(18).

PMID: 39336999 PMC: 11431936. DOI: 10.3390/jcm13185512.

Resveratrol suppresses hepatic fatty acid synthesis and increases fatty acid β-oxidation via the microRNA-33/SIRT6 signaling pathway.

Liu C, Pan X, Hao Z, Wang X, Wang C, Song G Exp Ther Med. 2024; 28(2):326.

PMID: 38979023 PMC: 11229395. DOI: 10.3892/etm.2024.12615.

Cholesterol metabolism: physiological regulation and diseases.

Guo J, Chen S, Zhang Y, Liu J, Jiang L, Hu L MedComm (2020). 2024; 5(2):e476.

PMID: 38405060 PMC: 10893558. DOI: 10.1002/mco2.476.

Regulation of ABCA1 by miR-33 and miR-34a in the Aging Eye.

Peters F, Grimm C Adv Exp Med Biol. 2023; 1415:55-59.

PMID: 37440014 DOI: 10.1007/978-3-031-27681-1_9.

Clearance of lipid droplets by chimeric autophagy-tethering compound ameliorates the age-related macular degeneration phenotype in mice lacking APOE.

Zhang Y, Huang J, Liang Y, Huang J, Fu Y, Chen N Autophagy. 2023; 19(10):2668-2681.

PMID: 37266932 PMC: 10472852. DOI: 10.1080/15548627.2023.2220540.

References

Xu Q, Cao S, Rajapakse S, Matsubara J . Understanding AMD by analogy: systematic review of lipid-related common pathogenic mechanisms in AMD, AD, AS and GN. Lipids Health Dis. 2018; 17(1):3. PMC: 5755337. DOI: 10.1186/s12944-017-0647-7. View

Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M . MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J Am Heart Assoc. 2013; 1(6):e003376. PMC: 3540673. DOI: 10.1161/JAHA.112.003376. View

Walker A, Jacobs R, Watts J, Rottiers V, Jiang K, Finnegan D . A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell. 2011; 147(4):840-52. PMC: 3384509. DOI: 10.1016/j.cell.2011.09.045. View

Storti F, Raphael G, Griesser V, Klee K, Drawnel F, Willburger C . Regulated efflux of photoreceptor outer segment-derived cholesterol by human RPE cells. Exp Eye Res. 2017; 165:65-77. DOI: 10.1016/j.exer.2017.09.008. View

Pennington K, Deangelis M . Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016; 3:34. PMC: 5178091. DOI: 10.1186/s40662-016-0063-5. View

Lyssenko N, Haider N, Picataggi A, Cipollari E, Jiao W, Phillips M . Directional ABCA1-mediated cholesterol efflux and apoB-lipoprotein secretion in the retinal pigment epithelium. J Lipid Res. 2018; 59(10):1927-1939. PMC: 6168305. DOI: 10.1194/jlr.M087361. View

Wang C, Zhang K, Aredo B, Lu H, Ufret-Vincenty R . Novel method for the rapid isolation of RPE cells specifically for RNA extraction and analysis. Exp Eye Res. 2012; 102:1-9. PMC: 3432720. DOI: 10.1016/j.exer.2012.06.003. View

Cao X, Shen D, Patel M, Tuo J, Johnson T, Olsen T . Macrophage polarization in the maculae of age-related macular degeneration: a pilot study. Pathol Int. 2011; 61(9):528-35. PMC: 3292787. DOI: 10.1111/j.1440-1827.2011.02695.x. View

Wang L, Li C, Rudolf M, Belyaeva O, Chung B, Messinger J . Lipoprotein particles of intraocular origin in human Bruch membrane: an unusual lipid profile. Invest Ophthalmol Vis Sci. 2008; 50(2):870-7. PMC: 2692837. DOI: 10.1167/iovs.08-2376. View

10.

Walker A, Yang F, Jiang K, Ji J, Watts J, Purushotham A . Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 2010; 24(13):1403-17. PMC: 2895199. DOI: 10.1101/gad.1901210. View

11.

Gnanaguru G, Choi A, Amarnani D, DAmore P . Oxidized Lipoprotein Uptake Through the CD36 Receptor Activates the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 2016; 57(11):4704-12. PMC: 5024668. DOI: 10.1167/iovs.15-18663. View

12.

Burgess S, Davey Smith G . Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. Ophthalmology. 2017; 124(8):1165-1174. PMC: 5526457. DOI: 10.1016/j.ophtha.2017.03.042. View

13.

Rayner K, Esau C, Hussain F, McDaniel A, Marshall S, van Gils J . Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature. 2011; 478(7369):404-7. PMC: 3235584. DOI: 10.1038/nature10486. View

14.

Davalos A, Goedeke L, Smibert P, Ramirez C, Warrier N, Andreo U . miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci U S A. 2011; 108(22):9232-7. PMC: 3107310. DOI: 10.1073/pnas.1102281108. View

15.

Reynolds R, Rosner B, Seddon J . Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology. 2010; 117(10):1989-95. PMC: 3081670. DOI: 10.1016/j.ophtha.2010.07.009. View

16.

Asare-Bediako B, Noothi S, Li Calzi S, Athmanathan B, Vieira C, Adu-Agyeiwaah Y . Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes. Cells. 2020; 9(2). PMC: 7072836. DOI: 10.3390/cells9020464. View

17.

Knickelbein J, Chan C, Sen H, Ferris F, Nussenblatt R . Inflammatory Mechanisms of Age-related Macular Degeneration. Int Ophthalmol Clin. 2015; 55(3):63-78. PMC: 4472429. DOI: 10.1097/IIO.0000000000000073. View

18.

Ishida B, Duncan K, Bailey K, Kane J, Schwartz D . High density lipoprotein mediated lipid efflux from retinal pigment epithelial cells in culture. Br J Ophthalmol. 2006; 90(5):616-20. PMC: 1857047. DOI: 10.1136/bjo.2005.085076. View

19.

Levy O, Calippe B, Lavalette S, Hu S, Raoul W, Dominguez E . Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age-related macular degeneration. EMBO Mol Med. 2015; 7(2):211-26. PMC: 4328649. DOI: 10.15252/emmm.201404524. View

20.

Johnson L, Forest D, Banna C, Radeke C, Maloney M, Hu J . Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration. Proc Natl Acad Sci U S A. 2011; 108(45):18277-82. PMC: 3215058. DOI: 10.1073/pnas.1109703108. View