Mechanisms for the therapeutic effect of fenofibrate on diabetic retinopathy and its clinical application_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Ying , Duan Ximei ,  Xu Jixiong

Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China (Liu Ying,now working at Department of Emergency);

Corresponding author：

Xu Jixiong, Email: xujixiong@163.com

Keywords：

Diabetic retinopathy/drug therapy; Fenofibrate/therapeutic use; Review

DOI：

10.3760/cma.j.issn.1005-1015.2017.02.026

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Chronic inflammation, oxidative stress and retinal ganglion cell apoptosis play important roles in the development of diabetic retinopathy. Fenofibrate, a peroxisome proliferator-activated receptor α agonist, is used for dyslipidemia. In addition to its lipid-modulating effects, fenofibrate also has anti-inflammatory, antioxidant, anti-apoptotic and anti-angiogenesis properties that may be useful to delay the progression of diabetic retinopathy. Some clinical studies have already confirmed that fenofibrate has therapeutic effect on diabetic retinopathy. Further studies the application of fenofibrate in the treatment of diabetic microangiopathy to clarify the safety and efficacy of fenofibrate is of great significance.

Citation： Liu Ying, Duan Ximei, Xu Jixiong. Mechanisms for the therapeutic effect of fenofibrate on diabetic retinopathy and its clinical application. Chinese Journal of Ocular Fundus Diseases, 2017, 33(2): 206-209. doi: 10.3760/cma.j.issn.1005-1015.2017.02.026 Copy

1.	Avery RL, Gordon GM. Systemic safety of prolonged monthly anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis[J]. JAMA Ophthalmol, 2015, 134(1): 21-29. DOI: 10.1001/jamaoph thalmol.2015.4070.
2.	Hu Y, Chen Y, Ding L, et al. Pathogenic role of diabetes-induced PPAR-alpha down-regulation in microvascular dysfunction[J]. Proc Natl Acad Sci USA, 2013, 110(38): 15401-15406. DOI: 10.1073/pnas.1307211110.
3.	Kasai T, Miyauchi K, Yokoyama T, et al. Efficacy of peroxisome proliferative activated receptor (PPAR)-alpha ligands, fenofibrate, on intimal hyperplasia and constrictive remodeling after coronary angioplasty in porcine models[J]. Atherosclerosis, 2006, 188(2): 274-280. DOI: 10.1016/j.atherosclerosis.2005.10.047.
4.	Cuzzocrea S. The role of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in the regulation of acute inflammation[J]. J Leukoc Biol, 2006, 79(5): 999-1010. DOI: 10.1189/jlb.0605341.
5.	Trudeau K, Roy S, Guo W, et al. Fenofibric acid reduces fibronectin and collagen type Ⅳ overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability[J]. Invest Ophthalmol Vis Sci, 2011, 52(9): 6348-6354. DOI: 10.1167/iovs.11-7282.
6.	Moran E, Ding L, Wang Z, et al. Protective and antioxidant effects of PPARα in the ischemic retina PPARα in retinal ischemia[J]. Invest Ophthalmol Vis Sci, 2014, 55(7): 4568-4576. DOI: 10.1167/iovs.13-13127.
7.	Romeo G, Liu WH, Asnaghi V, et al. Activation of nuclear factor-κB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes[J]. Diabetes, 2002, 51(7): 2241-2248. DOI: 10.2337/db11-0413.
8.	Chen Y, Hu Y, Lin M, et al. Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models[J]. Diabetes, 2013, 62(1): 261-272. DOI: 10.2337/db11-0413.
9.	Noureldein MH, Abd El-Razek RS, El-Hefnawy MH, et al. Fenofibrate reduces inflammation in obese patients with or without type 2 diabetes mellitus via sirtuin 1/fetuin A axis[J]. Diabetes Res Clin Pract, 2015, 109(3): 513-520. DOI: 10.1016/j.diabres. 2015.05.043.
10.	Hsu YJ, Wang LC, Yang WS, et al. Effects of fenofibrate on adiponectin expression in retinas of streptozotocin-induced diabetic rats[J/OL]. J Diabetes Res, 2014, 2014: 540326[2014-12-01]. . DOI: 10.1155/ 2014/540326.
11.	Villarroel M, Garcia-Ramirez M, Corraliza L, et al. Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1beta by suppressing AMP-activated protein kinase (AMPK) activation[J]. Diabetologia, 2011, 54(6): 1543-1553. DOI: 10.1007/s00125-011-2089-5.
12.	Kim J, Ahn JH, Kim JH, et al. Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway[J]. Exp Eye Res, 2007, 84(5): 886-893. DOI: 10.1016/j.exer.2007.01.009.
13.	Tomizawa A, Hattori Y, Inoue T, et al. Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate–activated protein kinase activation[J]. Metabolism, 2011, 60(4): 513-522. DOI: 10.1016/j.metabol.2010.04.020.
14.	Yang Y, Hayden MR, Sowers S, et al. Retinal redox stress and remodeling in cardiometabolic syndrome and diabetes[J]. Oxid Med Cell Longev, 2010, 3(6): 392-403. DOI: 10.4161/oxim.3.6.14786.
15.	Simó R, Hernández C. Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications[J]. Br J Ophthalmol, 2012, 96(10): 1285-1290. DOI: 10.1136/bjophthalmol-2012-302005.
16.	Cheung N, Wong TY. Fenofibrate and diabetic retinopathy[J]. The Lancet, 2008, 371(9614): 721-722. DOI: 10.1016/S0140-6736 (08)60333-5.
17.	Ding L, Cheng R, Hu Y, et al. Peroxisome proliferator-activated receptor alpha protects capillary pericytes in the retina[J]. Am J Pathol, 2014(10), 184: 2709-2720. DOI: 10.1016/j.ajpath. 2014.06.021.
18.	Olukman M, Sezer ED, Ulker S, et al. Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats[J/OL]. Exp Diabetes Res, 2010, 2010: 828531[2010-12-27]. . DOI: 10.1155/2010/828531.
19.	Lu Y, Cheng J, Chen L, et al. Endoplasmic reticulum stress involved in high-fat diet and palmitic acid-induced vascular damages and fenofibrate intervention[J]. Biochem Biophys Res Commun, 2015, 458(1): 1-7. DOI: 10.1016/j.bbrc.2014.12.123.
20.	Deplanque D, Gelé P, Pétrault O, et al. Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment[J]. J Neurosci, 2003, 23(15): 6264-6271.
21.	Bogdanov P, Hernandez C, Corraliza L, et al. Effect of fenofibrate on retinal neurodegeneration in an experimental model of type 2 diabetes[J]. Acta Diabetol, 2015, 52(1): 113-122. DOI: 10.1007/ s00592-014-0610-2.
22.	Cacicedo JM, Benjachareonwong S, Chou E, et al. Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3630-3639. DOI: 10.1167/iovs.10-5784.
23.	Vinores SA, Xiao WH, Aslam S, et al. Implication of the hypoxia response element of the VEGF promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development[J]. J Cell Physiol, 2006, 206(3): 749-758. DOI: 10.1002/jcp.20525.
24.	Zhou J, Zhang S, Xue J, et al. Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) suppresses hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in cancer cells[J]. J Biol Chem, 2012, 287(42): 35161-35169. DOI: 10.1074/jbc.M112.367367.
25.	Varet J, Vincent L, Mirshahi P, et al. Fenofibrate inhibits angiogenesis in vitro and in vivo[J]. Cell Mol Life Sci, 2003, 60(4): 810-819. DOI: 10.1007/s00018-003-2322-6.
26.	Zhao J, Geng YU, Hua H, et al. Fenofibrate inhibits the expression of VEGFC and VEGFR-3 in retinal pigmental epithelial cells exposed to hypoxia[J]. Exp Ther Med, 2015, 10(4): 1404-1412. DOI: 10.3892/etm.2015.2697.
27.	Wang Z, Moran E, Ding L, et al. PPARalpha regulates mobilization and homing of endothelial progenitor cells through the HIF-1alpha/SDF-1 pathway[J]. Invest Ophthalmol Vis Sci, 2014, 55(6): 3820-3832. DOI: 10.1167/iovs.13-13396.
28.	Gong Y, Shao Z, Fu Z, et al. Fenofibrate inhibits cytochrome P450 epoxygenase 2C activity to suppress pathological ocular angiogenesis[J]. E Bio Medicine, 2016, 13: 201-211. DOI: 10.1016/ j.ebiom.2016.09.025.
29.	Hiukka A, Maranghi M, Matikainen N, et al. PPAR-alpha: an emerging therapeutic target in diabetic microvascular damage[J]. Nat Rev Endocrinol, 2010, 6(8): 454-463. DOI: 10.1038/ nrendo.2010.89.
30.	Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial[J]. The Lancet, 2007, 370(9600): 1687-1697. DOI: 10.1016/S0140-6736(07)61607-9.
31.	Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes[J]. N Engl J Med, 2010, 363(3): 233-244. DOI: 10.1056/NEJMoa1001288.
32.	Massin P, Peto T, Ansquer JC, et al. Effects of fenofibric acid on diabetic macular edema: the MacuFen study[J]. Ophthalmic Epidemiol, 2014, 21(5): 307-317. DOI: 10.3109/09 286586. 2014.949783.
33.	Kalea AZ, Schmidt AM, Hudson BI. RAGE: a novel biological and genetic marker for vascular disease[J]. Clin Sci (Lond), 2009, 116(8): 621-637. DOI: 10.1042/CS20080494.
34.	Lindsey JB, Cipollone F, Abdullah SM, et al. Receptor for advanced glycation end-products (RAGE) and soluble RAGE (sRAGE): cardiovascular implications[J]. Diab Vasc Dis Res, 2009, 6(1): 7-14. DOI: 10.3132/dvdr.2009.002.
35.	Zong H, Ward M, Madden A, et al. Hyperglycaemia-induced pro-inflammatory responses by retinal müller glia are regulated by the receptor for advanced glycation end-products (RAGE)[J]. Diabetologia, 2010, 53(12): 2656-2666. DOI: 10.1007/s00125-010-1900-z.
36.	Harja E, Bu DX, Hudson BI, et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE^-/- mice[J]. J Clin Invest, 2008, 118(1): 183-194. DOI: 10.1172/ JCI32703.
37.	Lingam G, Wong TY. Systemic medical management of diabetic retinopathy[J]. Middle East Afr J Ophthalmol, 2013, 20(4): 301-308. DOI: 10.4103/0974-9233.120010.
38.	Balendiran GK, Rajkumar B. Fibrates inhibit aldose reductase activity in the forward and reverse reactions[J]. Biochem Pharmacol, 2005, 70(11): 1653-1663. DOI: 10.1016/j.bcp.2005.06.029.

1. Avery RL, Gordon GM. Systemic safety of prolonged monthly anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis[J]. JAMA Ophthalmol, 2015, 134(1): 21-29. DOI: 10.1001/jamaoph thalmol.2015.4070.
2. Hu Y, Chen Y, Ding L, et al. Pathogenic role of diabetes-induced PPAR-alpha down-regulation in microvascular dysfunction[J]. Proc Natl Acad Sci USA, 2013, 110(38): 15401-15406. DOI: 10.1073/pnas.1307211110.
3. Kasai T, Miyauchi K, Yokoyama T, et al. Efficacy of peroxisome proliferative activated receptor (PPAR)-alpha ligands, fenofibrate, on intimal hyperplasia and constrictive remodeling after coronary angioplasty in porcine models[J]. Atherosclerosis, 2006, 188(2): 274-280. DOI: 10.1016/j.atherosclerosis.2005.10.047.
4. Cuzzocrea S. The role of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in the regulation of acute inflammation[J]. J Leukoc Biol, 2006, 79(5): 999-1010. DOI: 10.1189/jlb.0605341.
5. Trudeau K, Roy S, Guo W, et al. Fenofibric acid reduces fibronectin and collagen type Ⅳ overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability[J]. Invest Ophthalmol Vis Sci, 2011, 52(9): 6348-6354. DOI: 10.1167/iovs.11-7282.
6. Moran E, Ding L, Wang Z, et al. Protective and antioxidant effects of PPARα in the ischemic retina PPARα in retinal ischemia[J]. Invest Ophthalmol Vis Sci, 2014, 55(7): 4568-4576. DOI: 10.1167/iovs.13-13127.
7. Romeo G, Liu WH, Asnaghi V, et al. Activation of nuclear factor-κB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes[J]. Diabetes, 2002, 51(7): 2241-2248. DOI: 10.2337/db11-0413.
8. Chen Y, Hu Y, Lin M, et al. Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models[J]. Diabetes, 2013, 62(1): 261-272. DOI: 10.2337/db11-0413.
9. Noureldein MH, Abd El-Razek RS, El-Hefnawy MH, et al. Fenofibrate reduces inflammation in obese patients with or without type 2 diabetes mellitus via sirtuin 1/fetuin A axis[J]. Diabetes Res Clin Pract, 2015, 109(3): 513-520. DOI: 10.1016/j.diabres. 2015.05.043.
10. Hsu YJ, Wang LC, Yang WS, et al. Effects of fenofibrate on adiponectin expression in retinas of streptozotocin-induced diabetic rats[J/OL]. J Diabetes Res, 2014, 2014: 540326[2014-12-01]. . DOI: 10.1155/ 2014/540326.
11. Villarroel M, Garcia-Ramirez M, Corraliza L, et al. Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1beta by suppressing AMP-activated protein kinase (AMPK) activation[J]. Diabetologia, 2011, 54(6): 1543-1553. DOI: 10.1007/s00125-011-2089-5.
12. Kim J, Ahn JH, Kim JH, et al. Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway[J]. Exp Eye Res, 2007, 84(5): 886-893. DOI: 10.1016/j.exer.2007.01.009.
13. Tomizawa A, Hattori Y, Inoue T, et al. Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate–activated protein kinase activation[J]. Metabolism, 2011, 60(4): 513-522. DOI: 10.1016/j.metabol.2010.04.020.
14. Yang Y, Hayden MR, Sowers S, et al. Retinal redox stress and remodeling in cardiometabolic syndrome and diabetes[J]. Oxid Med Cell Longev, 2010, 3(6): 392-403. DOI: 10.4161/oxim.3.6.14786.
15. Simó R, Hernández C. Neurodegeneration is an early event in diabetic retinopathy: therapeutic implications[J]. Br J Ophthalmol, 2012, 96(10): 1285-1290. DOI: 10.1136/bjophthalmol-2012-302005.
16. Cheung N, Wong TY. Fenofibrate and diabetic retinopathy[J]. The Lancet, 2008, 371(9614): 721-722. DOI: 10.1016/S0140-6736 (08)60333-5.
17. Ding L, Cheng R, Hu Y, et al. Peroxisome proliferator-activated receptor alpha protects capillary pericytes in the retina[J]. Am J Pathol, 2014(10), 184: 2709-2720. DOI: 10.1016/j.ajpath. 2014.06.021.
18. Olukman M, Sezer ED, Ulker S, et al. Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats[J/OL]. Exp Diabetes Res, 2010, 2010: 828531[2010-12-27]. . DOI: 10.1155/2010/828531.
19. Lu Y, Cheng J, Chen L, et al. Endoplasmic reticulum stress involved in high-fat diet and palmitic acid-induced vascular damages and fenofibrate intervention[J]. Biochem Biophys Res Commun, 2015, 458(1): 1-7. DOI: 10.1016/j.bbrc.2014.12.123.
20. Deplanque D, Gelé P, Pétrault O, et al. Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment[J]. J Neurosci, 2003, 23(15): 6264-6271.
21. Bogdanov P, Hernandez C, Corraliza L, et al. Effect of fenofibrate on retinal neurodegeneration in an experimental model of type 2 diabetes[J]. Acta Diabetol, 2015, 52(1): 113-122. DOI: 10.1007/ s00592-014-0610-2.
22. Cacicedo JM, Benjachareonwong S, Chou E, et al. Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes[J]. Invest Ophthalmol Vis Sci, 2011, 52(6): 3630-3639. DOI: 10.1167/iovs.10-5784.
23. Vinores SA, Xiao WH, Aslam S, et al. Implication of the hypoxia response element of the VEGF promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development[J]. J Cell Physiol, 2006, 206(3): 749-758. DOI: 10.1002/jcp.20525.
24. Zhou J, Zhang S, Xue J, et al. Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) suppresses hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in cancer cells[J]. J Biol Chem, 2012, 287(42): 35161-35169. DOI: 10.1074/jbc.M112.367367.
25. Varet J, Vincent L, Mirshahi P, et al. Fenofibrate inhibits angiogenesis in vitro and in vivo[J]. Cell Mol Life Sci, 2003, 60(4): 810-819. DOI: 10.1007/s00018-003-2322-6.
26. Zhao J, Geng YU, Hua H, et al. Fenofibrate inhibits the expression of VEGFC and VEGFR-3 in retinal pigmental epithelial cells exposed to hypoxia[J]. Exp Ther Med, 2015, 10(4): 1404-1412. DOI: 10.3892/etm.2015.2697.
27. Wang Z, Moran E, Ding L, et al. PPARalpha regulates mobilization and homing of endothelial progenitor cells through the HIF-1alpha/SDF-1 pathway[J]. Invest Ophthalmol Vis Sci, 2014, 55(6): 3820-3832. DOI: 10.1167/iovs.13-13396.
28. Gong Y, Shao Z, Fu Z, et al. Fenofibrate inhibits cytochrome P450 epoxygenase 2C activity to suppress pathological ocular angiogenesis[J]. E Bio Medicine, 2016, 13: 201-211. DOI: 10.1016/ j.ebiom.2016.09.025.
29. Hiukka A, Maranghi M, Matikainen N, et al. PPAR-alpha: an emerging therapeutic target in diabetic microvascular damage[J]. Nat Rev Endocrinol, 2010, 6(8): 454-463. DOI: 10.1038/ nrendo.2010.89.
30. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial[J]. The Lancet, 2007, 370(9600): 1687-1697. DOI: 10.1016/S0140-6736(07)61607-9.
31. Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes[J]. N Engl J Med, 2010, 363(3): 233-244. DOI: 10.1056/NEJMoa1001288.
32. Massin P, Peto T, Ansquer JC, et al. Effects of fenofibric acid on diabetic macular edema: the MacuFen study[J]. Ophthalmic Epidemiol, 2014, 21(5): 307-317. DOI: 10.3109/09 286586. 2014.949783.
33. Kalea AZ, Schmidt AM, Hudson BI. RAGE: a novel biological and genetic marker for vascular disease[J]. Clin Sci (Lond), 2009, 116(8): 621-637. DOI: 10.1042/CS20080494.
34. Lindsey JB, Cipollone F, Abdullah SM, et al. Receptor for advanced glycation end-products (RAGE) and soluble RAGE (sRAGE): cardiovascular implications[J]. Diab Vasc Dis Res, 2009, 6(1): 7-14. DOI: 10.3132/dvdr.2009.002.
35. Zong H, Ward M, Madden A, et al. Hyperglycaemia-induced pro-inflammatory responses by retinal müller glia are regulated by the receptor for advanced glycation end-products (RAGE)[J]. Diabetologia, 2010, 53(12): 2656-2666. DOI: 10.1007/s00125-010-1900-z.
36. Harja E, Bu DX, Hudson BI, et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE^-/- mice[J]. J Clin Invest, 2008, 118(1): 183-194. DOI: 10.1172/ JCI32703.
37. Lingam G, Wong TY. Systemic medical management of diabetic retinopathy[J]. Middle East Afr J Ophthalmol, 2013, 20(4): 301-308. DOI: 10.4103/0974-9233.120010.
38. Balendiran GK, Rajkumar B. Fibrates inhibit aldose reductase activity in the forward and reverse reactions[J]. Biochem Pharmacol, 2005, 70(11): 1653-1663. DOI: 10.1016/j.bcp.2005.06.029.

Previous Article
The current status and progress of ocriplasmin in treating vitreomacular interface diseases
Next Article
Suprachoroidal space drug delivery

Chinese Journal of Ocular Fundus Diseases

Mechanisms for the therapeutic effect of fenofibrate on diabetic retinopathy and its clinical application

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content