Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation
Low-density lipoprotein (LDL) cholesterol plays a causal role in the development of atherosclerotic cardiovascular disease (ASCVD). Activating the intracellular NAD⁺-dependent deacetylase Sirtuin-1 (SIRT1) through pharmacological means lowers plasma LDL-cholesterol levels by increasing the expression of hepatic LDL receptors (LDLR), a mechanism linked to protective effects against atherosclerosis.
A recent study published in Cardiovascular Research by Dr. Srividya Velagapudi and colleagues revealed that SIRT1 binds directly to hepatic PCSK9 and reduces its activity through deacetylation, thereby promoting LDL-cholesterol clearance via LDLR upregulation in the liver. Elevating circulating SIRT1 levels provides atheroprotective benefits in mice and high SIRT1 is associated with better outcomes in patients with established ASCVD.