SIRT-1 Activity Sustains Cholesterol Synthesis in the Brain

[Display omitted] •SIRT-1 inhibition with EX-527 downregulates SREBP-2 and HMGCR expression, and reduces cholesterol levels.•Cholesterol reduction occurs in neurons and astrocytes, and affects the synaptic content of this lipid.•SIRT-1 activity is required to sustain normal levels of cholesterol synthesis in the adult brain. SIRT-1 is a potent energy regulator that has been implicated in the aging of different tissues, and cholesterol synthesis demands high amounts of cellular adenosine triphosphate. An efficient synaptic transmission depends on processes that are highly influenced by cholesterol levels, like endocytosis, exocytosis and membrane lateral diffusion of neurotransmitter receptors. We set out to investigate whether SIRT-1 activity affects brain cholesterol metabolism. We found that pharmacological inhibition of SIRT-1 with EX-527 reduces the mRNA amounts of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR), Cytochrome P450 46A1 (CYP46A1) and Apolipoprotein E (APO-E) in rat primary cortical cultures. The decreased expression of these genes was paralleled by a significant reduction of the cholesterol levels in this type of neuronal culture. Interestingly, a cholesterol decrease of similar extent was observed in mouse astroglial cultures after EX-527 treatment. In agreement, mice administered with EX-527 for 5 days showed a down-regulation of cholesterol synthesis in the cortex, with significant reductions in the mRNA amounts of the transcription factor Sterol Regulatory Element Binding Protein 2 (SREBP-2) and the enzyme HMGCR, two key regulators of the cholesterol synthesis. These transcriptional changes were paralleled by reduced cholesterol levels at cortical synapses. SIRT-1 inhibition also reduced the amount of cholesterol in the hippocampus but without affecting the HMGCR expression levels. Altogether, these results uncover a role for SIRT-1 in the regulation of cholesterol metabolism, and demonstrate that SIRT-1 is required to sustain adequate levels of cholesterol synthesis in the adult brain.