Sirtuin 1 regulates lipid metabolism associated with optic nerve regeneration

Zhang,Yan; Li,Hongyang; Cao,Yongmei; Zhang,Maonian; Wei,Shihui

doi:10.3892/mmr.2015.4286

Sirtuin 1 regulates lipid metabolism associated with optic nerve regeneration

Authors:
- Yan Zhang
- Hongyang Li
- Yongmei Cao
- Maonian Zhang
- Shihui Wei
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Affiliations: Department of Ophthalmology, Chinese PLA General Hospital, Beijing 100085, P.R. China, Department of Ophthalmology, International Mongolion Hospital, Hohhot, Inner Mongolia 010065, P.R. China
Published online on: September 2, 2015 https://doi.org/10.3892/mmr.2015.4286
Pages: 6962-6968

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Abstract

Injury to the optic nerve may lead to axonal degeneration, followed by the gradual death of retinal ganglion cells (RGCs), which results in irreversible vision loss. In the present study the mechanism of optic nerve injury, and the following regeneration and repair processes associated with sirtuin 1 (SIRT1)‑regulated lipid metabolism were analyzed. In addition, the treatment of optic nerve injury using resveratrol was investigated. A rat model of optic nerve damage was prepared, and rats were divided into control, model and resveratrol groups. The model rats (with optic nerve damage) were treated with phosphate‑buffered saline or resveratrol once a day for seven, 14 and 21 days. The rats were then sacrificed and the optic nerve was dissected. The expression levels of SIRT1, sterol regulatory element‑binding protein 2 (SREBP‑2) and 3‑hydroxy‑3‑methylglutaryl‑CoA reductase (HMGCR) mRNA in the optic nerve were measured by reverse transcription‑quantitative polymerase chain reaction, and the protein expression of SIRT1, SREBP2 and HMGCR was evaluated by western blotting. In addition, the cholesterol level of the optic nerve was assessed. The retina was excised and the surviving RGCs were observed and counted. The morphology of the RGCs in the rat model of optic nerve injury changed; however, the degree of damage in rats treated with resveratrol was relatively small. The number of surviving RGCs and the cholesterol level in the RGCs from the model rats was observed to be restored by treatment with resveratrol following optic nerve damage. Additionally, the expression levels of SIRT1, SREBP‑2 and HMGCR mRNA and protein were restored by resveratrol treatment in the rats with optic nerve damage. Thus, resveratrol reversed certain features of the optic nerve injury damage via SIRT1 and SREBP‑2‑associated signaling pathways and the downstream regulated gene, HMGCR. Furthermore, resveratrol promoted cholesterol synthesis in, and repair of, RGCs. Therefore, SIRT1 may serve as a promising novel target for the treatment of optic nerve damage.

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1	Pernet V and Schwab ME: Lost in the jungle: New hurdles for optic nerve axon regeneration. Trends Neurosci. 37:381–387. 2014. View Article : Google Scholar : PubMed/NCBI
2	Pernet V, Hauswirth WW and Di Polo A: Extracellular signal-regulated kinase 1/2 mediates survival, but not axon regeneration, of adult injured central nervous system neurons in vivo. J Neurochem. 93:72–83. 2005. View Article : Google Scholar : PubMed/NCBI
3	Goldberg JL, Klassen MP, Hua Y and Barres BA: Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 296:1860–1864. 2002. View Article : Google Scholar : PubMed/NCBI
4	Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL, Lemmon VP and Goldberg JL: KLF family members regulate intrinsic axon regeneration ability. Science. 326:298–301. 2009. View Article : Google Scholar : PubMed/NCBI
5	Schwab ME: Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci. 11:799–811. 2010. View Article : Google Scholar : PubMed/NCBI
6	Yiu G and He Z: Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 7:617–627. 2006. View Article : Google Scholar : PubMed/NCBI
7	Guarente L and Franklin H: Epstein lecture: Sirtuins, aging and medicine. N Engl J Med. 364:2235–2244. 2011. View Article : Google Scholar : PubMed/NCBI
8	Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P and Auwerx J: AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 458:1056–1060. 2009. View Article : Google Scholar : PubMed/NCBI
9	Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, et al: Stressdependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 303:2011–2015. 2004. View Article : Google Scholar : PubMed/NCBI
10	Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM and Puigserver P: Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 434:113–118. 2005. View Article : Google Scholar : PubMed/NCBI
11	Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD and Garcia JA: Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 324:1289–1293. 2009. View Article : Google Scholar : PubMed/NCBI
12	Michan S: Acetylome regulation by sirtuins in the brain: From normal physiology to aging and pathology. Curr Pharm Des. 19:6823–6838. 2013. View Article : Google Scholar : PubMed/NCBI
13	Michan S, Li Y, Chou MM, Parrella E, Ge H, Long JM, Allard JS, Lewis K, Miller M, Xu W, et al: SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci. 30:9695–9707. 2010. View Article : Google Scholar : PubMed/NCBI
14	Donmez G, Wang D, Cohen DE and Guarente L: SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell. 142:320–332. 2010. View Article : Google Scholar : PubMed/NCBI
15	Jiang M, Wang J, Fu J, Du L, Jeong H, West T, Xiang L, Peng Q, Hou Z, Cai H, et al: Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med. 18:153–158. 2011. View Article : Google Scholar : PubMed/NCBI
16	Donmez G, Arun A, Chung CY, McLean PJ, Lindquist S and Guarente L: SIRT1 protects against α-synuclein aggregation by activating molecular chaperones. J Neurosci. 32:124–132. 2012. View Article : Google Scholar : PubMed/NCBI
17	Guarani V, Deflorian G, Franco CA, Krüger M, Phng LK, Bentley K, Toussaint L, Dequiedt F, Mostoslavsky R, Schmidt MH, et al: Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature. 473:234–238. 2011. View Article : Google Scholar : PubMed/NCBI
18	Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, et al: SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21:2644–2658. 2007. View Article : Google Scholar : PubMed/NCBI
19	Chen J, Michan S, Juan AM, Hurst CG, Hatton CJ, Pei DT, Joyal JS, Evans LP, Cui Z, Stahl A, et al: Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy. Angiogenesis. 16:985–992. 2013. View Article : Google Scholar : PubMed/NCBI
20	Michan S, Juan AM, Hurst CG, Cui Z, Evans LP, Hatton CJ, Pei DT, Ju M, Sinclair DA, Smith LE and Chen J: Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy. PLoS One. 9:e850312014. View Article : Google Scholar : PubMed/NCBI
21	Jiao X, Peng Y and Yang L: Minocycline protects retinal ganglion cells after optic nerve crush injury in mice by delaying autophagy and upregulating nuclear factor-κB2. Chin Med J (Engl). 127:1749–1754. 2014.
22	Bazan NG: Homeostatic regulation of photoreceptor cell integrity: Significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: The proctor lecture. Invest Ophthalmol Vis Sci. 48:4866–4881. 2007. View Article : Google Scholar : PubMed/NCBI
23	Bazan NG, Birkle DL and Reddy TS: Biochemical and nutritional aspects of the metabolism of polyunsaturated fatty acids and phospholipids in experimental models of retinal degeneration. Retinal Degeneration: Experimental and Clinical Studies. LaVail MM, Hollyfield JG and Anderson RE: 2. A.R. Liss; New York, NY: pp. 159–187. 1985
24	Scott BL and Bazan NG: Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc Natl Acad Sci USA. 86:2903–2907. 1989. View Article : Google Scholar : PubMed/NCBI
25	Gordon WC, Rodriguez de Turco EB and Bazan NG: Retinal pigment epithelial cells play a central role in the conservation of docosahexaenoic acid by photoreceptor cells after shedding and phagocytosis. Curr Eye Res. 11:73–83. 1992. View Article : Google Scholar : PubMed/NCBI
26	Hoffman DR, Boettcher JA and Diersen-Schade DA: Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: A review of randomized controlled trials. Prostaglandins Leukot Essent Fatty Acids. 81:151–158. 2009. View Article : Google Scholar : PubMed/NCBI
27	Anderson RE, Maude MB and Bok D: Low docosahexaenoic acid levels in rod outer segment membranes of mice with rds/peripherin and P216L peripherin mutations. Invest Ophthalmol Vis Sci. 42:1715–1720. 2001.PubMed/NCBI
28	Gordon WC and Bazan NG: Mediator lipidomics in ophthalmology: Targets for modulation in inflammation, neuro-protection and nerve regeneration. Curr Eye Res. 38:995–1005. 2013. View Article : Google Scholar : PubMed/NCBI
29	Bretillon L, Thuret G, Grégoire S, Acar N, Joffre C, Bron AM, Gain P and Creuzot-Garcher CP: Lipid and fatty acid profile of the retina, retinal pigment epithelium/choroid and the lacrimal gland and associations with adipose tissue fatty acids in human subjects. Exp Eye Res. 87:521–528. 2008. View Article : Google Scholar : PubMed/NCBI
30	Acar N, Berdeaux O, Grégoire S, Cabaret S, Martine L, Gain P, Thuret G, Creuzot-Garcher CP, Bron AM and Bretillon L: Lipid composition of the human eye: Are red blood cells a good mirror of retinal and optic nerve fatty acids? PLoS One. 7:e351022012. View Article : Google Scholar : PubMed/NCBI
31	Kabasawa S, Mori K, Horie-Inoue K, Gehlbach PL, Inoue S, Awata T, Katayama S and Yoneya S: Associations of cigarette smoking but not serum fatty acids with age-related macular degeneration in a Japanese population. Ophthalmology. 118:1082–1088. 2011. View Article : Google Scholar : PubMed/NCBI