Inhibition of SIRT-1 reduces brain cholesterol synthesis

MUCCIOLI GG; SODERO AO; OCTAVE JN

Córdoba

Congreso; XXXIII Congreso de la SAN; 2018

SAN

A reduction in the expression/activity of SIRT-1 has been observed during aging in different tissues. While SIRT-1 can regulate many cellular processes including metabolism, the particular role of SIRT-1 in brain cholesterol metabolism remains unknown. In an attempt to emulate SIRT-1 loss of function in the aging brain, we inhibited SIRT-1 in primary cortical cultures and C57BL/6 mice. Cortical cultures treated with 1 µM EX-527, a SIRT-1 cell-permeable specific inhibitor (IC50 = 98 nM), showed a significant reduction in the levels of cholesterol, without noticeable changes in the levels of oxysterols, the main cholesterol-derived metabolites. In order to better understand this effect, the expression of cholesterol-related genes was evaluated using quantitative RT-PCR. SIRT-1 inhibition induced a repression of three key genes related to cholesterol homeostasis: HMGCR (synthesis), CYP46A1 (catabolism) and Apo-E (transport). Furthermore, C57BL/6 mice treated for 5 days with 10 mg/kg of EX-527 exhibited a similar reduction in the cholesterol content within the hippocampus. Lower levels of cholesterol upon treatment with EX-527 were also detected in synapses purified from mouse cortices. The reduced cholesterol levels in vivo were accompanied by repression of the transcription factor SREBP-2 and its target gene HMGCR. Altogether, these results suggest that SIRT-1 sustains cholesterol synthesis in the brain, and influences the synaptic cholesterol content.