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Elizabeth P. moran, Yusuke Takahashi, Ying Chen, Jian-Xing Ma; Fenofibrate Protects Retinal Müller cells from Oxidative Stress in a PPAR-alpha and AMPK-Dependent Mechanism. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2239.
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Clinical trials identified that the PPARα agonist fenofibrate inhibits diabetic retinopathy, but the mechanism is unknown. Preliminary reports suggest that fenofibrate’s protective effect is AMPK-dependent and PPARα-independent in retinal endothelial cells, but evidence are circumstantial, and no downstream target of AMPK has been proposed. Furthermore, the effect of fenofibrate on retinal Müller cells, which are critical in the development of DR, is unknown.
We used 4-Hydroxynonenal to induce oxidative stress in human Müller cells and quantified fenofibrate protection using an MTT assay. We determined its dependence on PPARα and AMPK using small molecule inhibition. We used western blotting to determine expression of UCP2 and activation of AMPK and used adenoviral PPARα overexpression to determine whether these effects were a consequence of PPARα activation.
We identified that fenofibrate-mediated cytoprotection is AMPK and PPARα-dependent (fig 1). Moreover, both fenofibrate and PPARα overexpression activate AMPK(fig 2). We found that the mitochondrial uncoupling protein UCP2 is upregulated (fig 2).
Taken together, our data suggest that fenofibrate’s protective effect is AMPK and PPARα dependent. Furthermore, because both fenofibrate and PPARα overexpression activate AMPK, this event may be PPARα-specific. We have also identified for the first time that both fenofibrate and PPARα upregulate UCP2, which is known to inhibit neurodegeneration and also diabetic complications. UCP2 is stabilized by active AMPK, and we hypothesize that fenofibrate AMPK activation may be responsible for UCP2 upregulation.
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