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

Benny Liu,Chonglun Xie,James A Richardson,Stephen D Turley,John M Dietschy

doi:10.1194/jlr.m700125-jlr200

Benny Liu, Chonglun Xie + Show 3 more

Open Access

https://doi.org/10.1194/jlr.m700125-jlr200

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Abstract

These studies explored the roles of receptor-mediated 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 LDL-cholesterol varied from 514 microg/day in the liver to zero in the central nervous system. In animals lacking LDL receptors, liver uptake remained about the same (411 microg/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 receptor-mediated 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 syndrome.

Highlights

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
To sort out the various processes that result in the tissue uptake of circulating total cholesterol carried in LDL (LDL-TC), the rates of clearance of homologous mouse LDL by the organs of the control ldlr1/1/npc11/1 animals were first measured
When organ weights (Fig. 2B) and the plasma LDL-TC concentration were taken into consideration, the uptake of cholesterol carried in LDL overwhelmingly took place in the liver

Summary

Introduction

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. 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. The general outline of this clathrin-coated pit pathway is understood, there are several major quantitative details that are still poorly defined but that may be important in understanding the pathophysiology of such diverse diseases as familial These apoE- and apoB-100-containing particles that reach the pericellular space compete for binding to low density lipoprotein receptors (LDLRs) on the plasma membrane of the various cells (Fig. 1, step A) [6, 7].

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