title: Fenoﬁbrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway.
abstract: Inﬂammation is a major contributing factor in the development of diabetic microvascular complications, regardless of whether improved glycaemic control is achieved. Studies have increasingly indicated that fenoﬁbrate, a lipid‑lowering therapeutic agent in clinical use, exerts a potential anti‑inﬂammatory effect, which is mediated by sirtuin 1 (SIRT1; an NAD+‑dependent deacetylase) in endothelial cells. The aim of the present study was to investigate the inhibitory effect of fenoﬁbrate on metabolic memory (via the regulation of SIRT1), and inflammatory responses in cell and animal models of diabetic retinopathy (DR). The data demonstrated that high glucose treatment in human retinal endothelial cells (HRECs) inhibited the expression and deacetylase activity of SIRT1. The reduction of SIRT1 expression and deacetylase activity persisted following a return to normal glucose levels. Furthermore, nuclear factor‑κB expression was observed to be negatively correlated with SIRT1 expression and activity in HRECs under high glucose levels and the subsequent return to normal glucose levels. Fenoﬁbrate treatment abrogated these changes. Knockdown of SIRT1 attenuated the effect of fenoﬁbrate on high glucose‑induced NF‑κB expression. In addition, fenoﬁbrate upregulated SIRT1 expression through peroxisome proliferator‑activated receptor α in high glucose‑induced metabolic memory. These findings indicate that fenoﬁbrate is important in anti‑inflammatory processes and suppresses the cellular metabolic memory of high glucose‑induced stress via the SIRT1‑dependent signalling pathway. Thus, treatment with fenofibrate may offer a promising therapeutic strategy for halting the development of DR and other complications of diabetes.
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Lishui City Center Hospital, Lishui, Zhejiang 323000, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200080, P.R. China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zheng
mesh_terms: D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D047493:PPAR alpha; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005947:Glucose; D011345:Fenofibrate