Statins and ALS: the possible role of impaired LXR signaling

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are commonly used in the therapy of cardiovascular diseases. Recent studies suggest that statins may induce amyotrophic lateral sclerosis (ALS) in some patients, but no pathogenic mechanism has been proposed for this association. Herein the hypothesis is proposed that statins may induce or aggravate ALS by impairing liver X receptor (LXR) signaling. The hypothesis is supported by the following observations: 1) statins inhibit the synthesis of endogenous LXR agonists, oxysterols, and decrease the expression of LXR target genes in many cells, 2) mice lacking LXRbeta exhibit sn ALS-like phenotype, 3) statins increase the concentration of plant sterols in plasma and tissues, partially by impairing LXR-dependent signaling, which results in augmented intestinal absorption and impaired biliary excretion of plant sterols, and 4) some plant sterols are toxic to motor neurons of the spinal cord, which are primarily affected in ALS patients. If this hypothesis is confirmed, LXR agonists could be used together with statins in patients predisposed to develop ALS or in those known to have the disorder to prevent motor neuron degeneration.