SIRT1 activation alleviates brain microvascular endothelial dysfunction in peroxisomal disorders.

Peroxisomal disorders are genetically heterogeneous metabolic disorders associated with a deficit of very long chain fatty acid β‑oxidation that commonly manifest as early‑onset neurodegeneration. Brain microvascular endothelial dysfunction with increased permeability to monocytes has been described in X‑linked adrenoleukodystrophy, one of the most common peroxisomal disorders caused by mutations of the ATP binding cassette subfamily D member 1 (ABCD1) gene. The present study demonstrated that dysregulation of sirtuin 1 (SIRT1) in human brain microvascular endothelial cells (HBMECs) mediates changes in adhesion molecules and tight‑junction protein expression, as well as increased adhesion to monocytes associated with peroxisomal dysfunction due to ABCD1 or hydroxysteroid 17‑β dehydrogenase 4 silencing. Furthermore, enhancement of the function of SIRT1 by resveratrol attenuated this molecular and functional dysregulation of HBMECs via modulation of the nuclear factor‑κB and Krüppel‑like factor 4 signaling pathways.