Delineation of metabolic responses of Npc1-/-nih mice lacking the cholesterol-esterifying enzyme SOAT2 to acute treatment with 2-hydroxypropyl-β-cyclodextrin.

Lipids present in lipoproteins cleared from the circulation are processed sequentially by three major proteins within the late endosomal/lysosomal (E/L) compartment of all cells: lysosomal acid lipase (LAL), Niemann-Pick (NPC) C2 and NPC1. When all three of these proteins are functioning normally, unesterified cholesterol (UC) exits the E/L compartment and is used in plasma membrane maintenance and various pathways in the endoplasmic reticulum including esterification by sterol O-acyltransferase 2 (SOAT2) or SOAT1 depending partly on cell type. Mutations in either NPC2 or NPC1 result in continual entrapment of UC and glycosphingolipids leading to neurodegeneration, pulmonary dysfunction, splenomegaly and liver damage. To date, the most effective agent for promoting release of entrapped UC in nearly all organs of NPC1-deficient mice and cats is 2-hydroxypropyl-β-cyclodextrin (2HPβCD). The cytotoxic nature of the liberated UC triggers various defenses including suppression of sterol synthesis and increased esterification. The present studies, using the Npc1-/-nih mouse model, measured the comparative quantitative importance of these two responses in the liver versus the spleen of Npc1-/-: Soat2+/+ and Npc1-/-: Soat2-/- mice in the 24 h following a single acute treatment with 2HPβCD. In the liver but not the spleen of both types of mice suppression of synthesis alone or in combination with increased esterification provided the major defense against the rise in unsequestered cellular UC content. These findings have implications for systemic 2HPβCD treatment in NPC1 patients in view of the purportedly low levels of SOAT2 activity in human liver.