Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease

Abstract

These studies explored the roles of receptormediated and bulk-phase endocytosis as well as macrophage infiltration in the accumulation of cholesterol in the mouse with Niemann-Pick type C (NPC) disease. Uptake of LDLcholesterol varied from 514 mg/day in the liver to zero in the central nervous system. In animals lacking LDL receptors, liver uptake remained about the same (411 mg/day), but more cholesterol was taken up in extrahepatic organs. This uptake was unaffected by the reductive methylation of LDL and consistent with bulk-phase endocytosis. All tissues accumulated cholesterol in mice lacking NPC1 function, but this accumulation was decreased in adrenal, unchanged in liver, and increased in organs like spleen and lung when LDL receptor function was also deleted. Over 56 days, the spleen and lung accumulated amounts of cholesterol greater than predicted, and these organs were heavily infiltrated with macrophages. This accumulation of both cholesterol and macrophages was increased by deleting LDL receptor function.These observations indicate that both receptormediated and bulk-phase endocytosis of lipoproteins, as well as macrophage infiltration, contribute to the cholesterol accumulation seen in NPC disease. These macrophages may also play a role in parenchymal cell death in this

Genetic variations and treatments that affect the lifespan of the NPC1 mouse

“…3C). In the first instance, increased delivery of cholesterol carried in chylomicrons to the liver worsened the hepatic disease (8), whereas in the second instance, deletion of LDLR activity increased the delivery of cholesterol carried in LDL to the lungs and worsened pulmonary function (16). Neither manipulation, however, is known to alter cholesterol flux across the blood-brain barrier.…”

“…In one experiment, 56-day-old animals were used to measure the weight and cholesterol concentration in different organs, and plasma was obtained to measure liver function tests (8,16).…”

ABCA1 plays no role in the centripetal movement of cholesterol from peripheral tissues to the liver and intestine in the mouse

“…This renewal process is apparently so important that virtually every cell in the body has invested in the complex biochemical machinery necessary to convert acetyl-CoA into cholesterol (9,10). Lesser amounts of sterol are also acquired through the receptor-mediated and bulk phase uptake of lipoproteins like LDL (11,12). However, as the pool of cholesterol in every tissue is essentially constant over a lifetime, and as no cell can degrade the sterol nucleus, it necessarily follows that each day an amount of cholesterol equal to that synthesized and acquired from LDL must leave the tissue and be transported to the endocrine glands and, more importantly, to the liver for excretion from the body.…”

Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 −/− mouse

“…Pathologically, this C accumulation is associated with infiltration of activated macrophages into many organs and with parenchymal cell death. In both the human and the mouse, these histological changes, in turn, result in the clinical syndromes of pulmonary failure, liver dysfunction, and progressive neurological disease (3,8). Importantly, in a particular organ, the severity of disease is proportional to the amount of C sequestered in that tissue (3,9,10).…”

“…These 2 proteins normally act in concert to facilitate the movement of unesterified cholesterol (C), derived from the cellular uptake of lipoproteins, across the limiting membrane of the lysosome to the metabolically active pool of sterol in the cytosolic compartment (3,4). As a consequence of these mutations, C progressively accumulates in the late endosomal/lysosomal (E/L) compartment of virtually every cell in the body from the time of early fetal development until death of the child or animal (5).…”