The role of 7-ketocholesterol in age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Yang Chen ,  Yin Lili

Department of Ophthalmology, The General Hospital of Shanghai, Shanghai JiaoTong University, Shanghai 200080, China;

Corresponding author：

Yin Lili, Email: yll144@aliyun.com

Keywords：

Macular degeneration/etiology; Inflammation; Cholesterol, LDL; Membrane lipids; Review

DOI：

10.3760/cma.j.issn.1005-1015.2017.06.031

Video：

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The hallmark lesions of age-related macular degeneration (AMD) are drusen and basal linear deposit which are lipid substances deposited in Bruch membrane or the compartment on the Bruch membrane. There is a prevailing hypothesis that lipid and its oxidized derivant deposited in retina may have important roles in the pathogenesis of AMD. Lipid oxidation products are toxic, may affect the adjacent cells, induce inflammation, and trigger neovascularization.7-ketocholestoral (7KCh), a naturally occurring oxidized form of cholesterol, had been found to be toxic to retinal cells and able to induce chronic inflammation, which may play a critical role in the development of AMD. However the precise mechanism remains to be elucidated. Thus we will make a brief review of 7KCh and its association with AMD.

Citation： Yang Chen, Yin Lili. The role of 7-ketocholesterol in age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2017, 33(6): 659-661. doi: 10.3760/cma.j.issn.1005-1015.2017.06.031 Copy

1.	Vingerling JR, Dielemans I, Bots ML, et al. Age-related macular degeneration is associated with atherosclerosis: the rotterdam study[J]. Am J Epidemiol, 1995, 142(4): 404-409.
2.	Vavvas DG, Daniels AB, Kapsala ZG, et al. Regression of some high-risk features of age-related macular degeneration (AMD) in patients receiving intensive statin treatment[J]. EBioMedicine, 2016, 5: 198-203.DOI: 10.1016/j.ebiom.2016.01.033.
3.	Mullins RF, Russell SR, Anderson DH, et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease[J]. FASEB J, 2000, 14(7): 835-846.
4.	Luchetti F, Canonico B, Cesarini E, et al. 7-ketocholesterol and 5,6-secosterol induce human endothelial cell dysfunction by differential mechanisms[J]. Steroids, 2015, 99(Pt B): 204-211.DOI: 10.1016/j.steroids.2015.02.008.
5.	Chang MC, Chen YJ, Liou EJ, et al. 7-ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells[J]. Oncotarget, 2016, 7(46): 74473-74483.DOI: 10.18632/oncotarget.12578.
6.	Rodriguez IR, Clark ME, Lee JW, et al. 7-ketocholesterol accumulates in ocular tissues as a consequence of aging and is present in high levels in drusen[J]. Exp Eye Res, 2014, 128: 151-155.DOI: 10.1016/j.exer.2014.09.009.
7.	EF M, IM L, JW L, et al. 7-ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation[J]. Invest Ophthalmol Vis Sci, 2009, 50(2): 523-532.DOI: 10.1167/iovs.08-2373.
8.	Dzeletovic S, Babiker A, Lund E, et al. Time course of oxysterol formation during in vitro oxidation of low density lipoprotein[J]. Chem Phys Lipids, 1995, 78(2): 119-128.
9.	Kritharides L, Kus M, Brown AJ, et al. Hydroxypropyl-beta-cyclodextrin-mediated efflux of 7-ketocholesterol from macrophage foam cells[J]. J Biol Chem, 1996, 271(44): 27450-27455.
10.	Rodriguez IR, Fliesler SJ. Photodamage generates 7-keto- and 7-hydroxycholesterol in the rat retina via a free radical-mediated mechanism[J]. Photochem Photobiol, 2009, 85(5): 1116-1125.DOI: 10.1111/j.1751-1097.2009.00568.x.
11.	Huang JD, Amaral J, Lee JW, et al. Sterculic acid antagonizes 7-ketocholesterol-mediated inflammation and inhibits choroidal neovascularization[J]. Biochim Biophys Acta, 2012, 1821(4): 637-646.DOI: 10.1016/j.bbalip.2012.01.013.
12.	Yin LL, Shi YH, Liu XJ, et al. A rat model for studying the biological effects of circulating LDL in the choriocapillaris-BrM-RPE complex[J]. Am J Pathol, 2012, 180(2): 541-549.DOI: 10.1016/j.ajpath.2011.10.015.
13.	Gordiyenko N, Campos M, Lee JW, et al. RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo[J]. Invest Ophthalmol Vis Sci, 2004, 45(8): 2822-2829.DOI: 10.1167/iovs.04-0074.
14.	Gillotte KL, Horkko S, Witztum JL, et al. Oxidized phospholipids, linked to apolipoprotein B of oxidized LDL, are ligands for macrophage scavenger receptors[J]. J Lipid Res, 2000, 41(5): 824-833.
15.	Rodriguez IR, Alam S, Lee JW. Cytotoxicity of oxidized low-density lipoprotein in cultured RPE cells is dependent on the formation of 7-ketocholesterol[J]. Invest Ophthalmol Vis Sci, 2004, 45(8): 2830-2837.DOI: 10.1167/iovs.04-0075.
16.	Hughes H, Mathews B, Lenz ML, et al. Cytotoxicity of oxidized LDL to porcine aortic smooth muscle cells is associated with the oxysterols 7-ketocholesterol and 7-hydroxycholesterol[J]. Arterioscler Thromb, 1994, 14(7): 1177-1185.
17.	Indaram M, Ma W, Zhao L, et al. 7-ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration[J]. Sci Rep, 2015, 5: 9144.DOI: 10.1038/srep09144.
18.	Huang JD, Presley JB, Chimento MF, et al. Age-related changes in human macular Bruch’s membrane as seen by quick-freeze/deep-etch[J]. Exp Eye Res, 2007, 85(2): 202-218.DOI: 10.1016/j.exer.2007.03.011.
19.	Pauleikhoff D, Harper CA, Marshall J, et al. Aging changes in Bruch’s membrane: a histochemical and morphologic study[J]. Ophthalmology, 1990, 97(2): 171-178.
20.	Albert AD, Boesze-Battaglia K. The role of cholesterol in rod outer segment membranes[J]. Prog Lipid Res, 2005, 44(2-3): 99-124.DOI: 10.1016/j.plipres.2005.02.001.
21.	Curcio CA, Messinger JD, Sloan KR, et al. Subretinal drusenoid deposits in non-neovascular age-related macular degeneration: morphology, prevalence, topography, and biogenesis model[J]. Retina, 2013, 33(2): 265-276.DOI: 10.1097/IAE.0b013e31827e25e0.
22.	Curcio CA, Millican CL, Bailey T, et al. Accumulation of cholesterol with age in human Bruch’s membrane[J]. Invest Ophthalmol Vis Sci, 2001, 42(1): 265-274.
23.	Yu DY, Cringle SJ. Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease[J]. Prog Retin Eye Res, 2001, 20(2): 175-208.
24.	Xu L, Sheflin LG, Porter NA, et al. 7-dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome[J]. Biochim Biophys Acta, 2012, 1821(6): 877-883.DOI: 10.1016/j.bbalip.2012.03.001.
25.	Qiu YT, Yuan Y, Wei Z, et al. Oxidized LDL induces apoptosis of human retinal pigment epithelium through activation of ERK-Bax/Bcl-2 signaling pathways[J]. Curr Eye Res, 2015, 40(4): 415-422.DOI: 10.3109/02713683.2014.927507.
26.	Yin LL, Wu XW, Gong YY, et al. Ox-LDL up-regulates the vascular endothelial growth factor-to-pigment epithelium-derived factor ratio in human retinal pigment epithelial cells[J]. Curr Eye Res, 2011, 36(4): 379-385.DOI: 10.3109/02713683.2010.537427.
27.	Gramajo AL, Zacharias LC, Neekhra A, et al. Mitochondrial DNA damage induced by 7-ketocholesterol in human retinal pigment epithelial cells in vitro[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1164-1170.DOI: 10.1167/iovs.09-3443.
28.	IM L, JD H, JW L, et al. 7-ketocholesterol-induced inflammation: involvement of multiple kinase signaling pathways via NFkappaB but independently of reactive oxygen species formation[J]. Invest Ophthalmol Vis Sci, 2010, 51(10): 4942-4955. DOI: 10.1167/iovs.09-4854.
29.	Shi G, Chen S, Wandu WS, et al. Inflammasomes Induced by 7-ketocholesterol and other stimuli in RPE and in bone marrow-derived cells differ markedly in their production of IL-1beta and IL-18[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1658-1664.DOI: 10.1167/iovs.14-14557.
30.	Ong JM, Aoki AM, Seigel GM, et al. Oxysterol-induced toxicity in R28 and ARPE-19 cells[J]. Neurochem Res, 2003, 28(6): 883-891.
31.	Dasari B, Prasanthi JR, Meiers C, et al. Differential effects of the estrogen receptor agonist estradiol on toxicity induced by enzymatically-derived or autoxidation-derived oxysterols in human ARPE-19 cells[J]. Curr Eye Res, 2013, 38(11): 1159-1171.DOI: 10.3109/02713683.2013.811257.
32.	Lee JW, Huang JD, Rodriguez IR. Extra-hepatic metabolism of 7-ketocholesterol occurs by esterification to fatty acids via cPLA2alpha and SOAT1 followed by selective efflux to HDL[J]. Biochim Biophys Acta, 2015, 1851(5): 605-619.DOI: 10.1016/j.bbalip.2015.01.007.
33.	Olivier E, Dutot M, Regazzetti A, et al. P2X7-pannexin-1 and amyloid beta-induced oxysterol input in human retinal cell: role in age-related macular degeneration?[J]. Biochimie, 2016, 127: 70-78.DOI: 10.1016/j.biochi.2016.04.014.
34.	Amaral J, Lee JW, Chou J, et al. 7-ketocholesterol induces inflammation and angiogenesis in vivo: a novel rat model[J]. PLoS One, 2013, 8(2): 56099[2013-02-08]. http://dx.plos.org/10.1371/journal.pone.0056099. DOI: 10.1371/journal.pone.0056099.

1. Vingerling JR, Dielemans I, Bots ML, et al. Age-related macular degeneration is associated with atherosclerosis: the rotterdam study[J]. Am J Epidemiol, 1995, 142(4): 404-409.
2. Vavvas DG, Daniels AB, Kapsala ZG, et al. Regression of some high-risk features of age-related macular degeneration (AMD) in patients receiving intensive statin treatment[J]. EBioMedicine, 2016, 5: 198-203.DOI: 10.1016/j.ebiom.2016.01.033.
3. Mullins RF, Russell SR, Anderson DH, et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease[J]. FASEB J, 2000, 14(7): 835-846.
4. Luchetti F, Canonico B, Cesarini E, et al. 7-ketocholesterol and 5,6-secosterol induce human endothelial cell dysfunction by differential mechanisms[J]. Steroids, 2015, 99(Pt B): 204-211.DOI: 10.1016/j.steroids.2015.02.008.
5. Chang MC, Chen YJ, Liou EJ, et al. 7-ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells[J]. Oncotarget, 2016, 7(46): 74473-74483.DOI: 10.18632/oncotarget.12578.
6. Rodriguez IR, Clark ME, Lee JW, et al. 7-ketocholesterol accumulates in ocular tissues as a consequence of aging and is present in high levels in drusen[J]. Exp Eye Res, 2014, 128: 151-155.DOI: 10.1016/j.exer.2014.09.009.
7. EF M, IM L, JW L, et al. 7-ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation[J]. Invest Ophthalmol Vis Sci, 2009, 50(2): 523-532.DOI: 10.1167/iovs.08-2373.
8. Dzeletovic S, Babiker A, Lund E, et al. Time course of oxysterol formation during in vitro oxidation of low density lipoprotein[J]. Chem Phys Lipids, 1995, 78(2): 119-128.
9. Kritharides L, Kus M, Brown AJ, et al. Hydroxypropyl-beta-cyclodextrin-mediated efflux of 7-ketocholesterol from macrophage foam cells[J]. J Biol Chem, 1996, 271(44): 27450-27455.
10. Rodriguez IR, Fliesler SJ. Photodamage generates 7-keto- and 7-hydroxycholesterol in the rat retina via a free radical-mediated mechanism[J]. Photochem Photobiol, 2009, 85(5): 1116-1125.DOI: 10.1111/j.1751-1097.2009.00568.x.
11. Huang JD, Amaral J, Lee JW, et al. Sterculic acid antagonizes 7-ketocholesterol-mediated inflammation and inhibits choroidal neovascularization[J]. Biochim Biophys Acta, 2012, 1821(4): 637-646.DOI: 10.1016/j.bbalip.2012.01.013.
12. Yin LL, Shi YH, Liu XJ, et al. A rat model for studying the biological effects of circulating LDL in the choriocapillaris-BrM-RPE complex[J]. Am J Pathol, 2012, 180(2): 541-549.DOI: 10.1016/j.ajpath.2011.10.015.
13. Gordiyenko N, Campos M, Lee JW, et al. RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo[J]. Invest Ophthalmol Vis Sci, 2004, 45(8): 2822-2829.DOI: 10.1167/iovs.04-0074.
14. Gillotte KL, Horkko S, Witztum JL, et al. Oxidized phospholipids, linked to apolipoprotein B of oxidized LDL, are ligands for macrophage scavenger receptors[J]. J Lipid Res, 2000, 41(5): 824-833.
15. Rodriguez IR, Alam S, Lee JW. Cytotoxicity of oxidized low-density lipoprotein in cultured RPE cells is dependent on the formation of 7-ketocholesterol[J]. Invest Ophthalmol Vis Sci, 2004, 45(8): 2830-2837.DOI: 10.1167/iovs.04-0075.
16. Hughes H, Mathews B, Lenz ML, et al. Cytotoxicity of oxidized LDL to porcine aortic smooth muscle cells is associated with the oxysterols 7-ketocholesterol and 7-hydroxycholesterol[J]. Arterioscler Thromb, 1994, 14(7): 1177-1185.
17. Indaram M, Ma W, Zhao L, et al. 7-ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration[J]. Sci Rep, 2015, 5: 9144.DOI: 10.1038/srep09144.
18. Huang JD, Presley JB, Chimento MF, et al. Age-related changes in human macular Bruch’s membrane as seen by quick-freeze/deep-etch[J]. Exp Eye Res, 2007, 85(2): 202-218.DOI: 10.1016/j.exer.2007.03.011.
19. Pauleikhoff D, Harper CA, Marshall J, et al. Aging changes in Bruch’s membrane: a histochemical and morphologic study[J]. Ophthalmology, 1990, 97(2): 171-178.
20. Albert AD, Boesze-Battaglia K. The role of cholesterol in rod outer segment membranes[J]. Prog Lipid Res, 2005, 44(2-3): 99-124.DOI: 10.1016/j.plipres.2005.02.001.
21. Curcio CA, Messinger JD, Sloan KR, et al. Subretinal drusenoid deposits in non-neovascular age-related macular degeneration: morphology, prevalence, topography, and biogenesis model[J]. Retina, 2013, 33(2): 265-276.DOI: 10.1097/IAE.0b013e31827e25e0.
22. Curcio CA, Millican CL, Bailey T, et al. Accumulation of cholesterol with age in human Bruch’s membrane[J]. Invest Ophthalmol Vis Sci, 2001, 42(1): 265-274.
23. Yu DY, Cringle SJ. Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease[J]. Prog Retin Eye Res, 2001, 20(2): 175-208.
24. Xu L, Sheflin LG, Porter NA, et al. 7-dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome[J]. Biochim Biophys Acta, 2012, 1821(6): 877-883.DOI: 10.1016/j.bbalip.2012.03.001.
25. Qiu YT, Yuan Y, Wei Z, et al. Oxidized LDL induces apoptosis of human retinal pigment epithelium through activation of ERK-Bax/Bcl-2 signaling pathways[J]. Curr Eye Res, 2015, 40(4): 415-422.DOI: 10.3109/02713683.2014.927507.
26. Yin LL, Wu XW, Gong YY, et al. Ox-LDL up-regulates the vascular endothelial growth factor-to-pigment epithelium-derived factor ratio in human retinal pigment epithelial cells[J]. Curr Eye Res, 2011, 36(4): 379-385.DOI: 10.3109/02713683.2010.537427.
27. Gramajo AL, Zacharias LC, Neekhra A, et al. Mitochondrial DNA damage induced by 7-ketocholesterol in human retinal pigment epithelial cells in vitro[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1164-1170.DOI: 10.1167/iovs.09-3443.
28. IM L, JD H, JW L, et al. 7-ketocholesterol-induced inflammation: involvement of multiple kinase signaling pathways via NFkappaB but independently of reactive oxygen species formation[J]. Invest Ophthalmol Vis Sci, 2010, 51(10): 4942-4955. DOI: 10.1167/iovs.09-4854.
29. Shi G, Chen S, Wandu WS, et al. Inflammasomes Induced by 7-ketocholesterol and other stimuli in RPE and in bone marrow-derived cells differ markedly in their production of IL-1beta and IL-18[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1658-1664.DOI: 10.1167/iovs.14-14557.
30. Ong JM, Aoki AM, Seigel GM, et al. Oxysterol-induced toxicity in R28 and ARPE-19 cells[J]. Neurochem Res, 2003, 28(6): 883-891.
31. Dasari B, Prasanthi JR, Meiers C, et al. Differential effects of the estrogen receptor agonist estradiol on toxicity induced by enzymatically-derived or autoxidation-derived oxysterols in human ARPE-19 cells[J]. Curr Eye Res, 2013, 38(11): 1159-1171.DOI: 10.3109/02713683.2013.811257.
32. Lee JW, Huang JD, Rodriguez IR. Extra-hepatic metabolism of 7-ketocholesterol occurs by esterification to fatty acids via cPLA2alpha and SOAT1 followed by selective efflux to HDL[J]. Biochim Biophys Acta, 2015, 1851(5): 605-619.DOI: 10.1016/j.bbalip.2015.01.007.
33. Olivier E, Dutot M, Regazzetti A, et al. P2X7-pannexin-1 and amyloid beta-induced oxysterol input in human retinal cell: role in age-related macular degeneration?[J]. Biochimie, 2016, 127: 70-78.DOI: 10.1016/j.biochi.2016.04.014.
34. Amaral J, Lee JW, Chou J, et al. 7-ketocholesterol induces inflammation and angiogenesis in vivo: a novel rat model[J]. PLoS One, 2013, 8(2): 56099[2013-02-08]. http://dx.plos.org/10.1371/journal.pone.0056099. DOI: 10.1371/journal.pone.0056099.

Chinese Journal of Ocular Fundus Diseases

The role of 7-ketocholesterol in age-related macular degeneration

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