Basic and Clinical Observations of Mevalonate Depletion on the Mevalonate Signaling Pathway

Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by pharmaceuticals, commonly referred to as statins, has proven to be an effective and efficient way in reducing cholesterol levels in patients. As a result of this intervention, mevalonate production, formed during cholesterol synthesis, is inhibited. Mevalonate is the precursor to a variety of crucial downstream products, including those involved with the mitochondrial electron transport chain, and localized activation of small GTPases. Statins have also been observed to induce changes of the immune system, favouring a reduced proinflammatory phenotype. However, near complete cessation of mevalonate and its downstream products have severe pro-inflammatory consequences as evident by patients suffering from mevalonate kinase deficiency who have increased inflammasome activity. It is evident that mevalonate production is a pivotal component of normal homeostatic cell processing, especially in maintaining a muted inflammatory response.