Gadolinium Chloride Rescues Niemann⁻Pick Type C Liver Damage.

Andrés Klein,Cristian Cortez,Silvana Zanlungo,Juan Oyarzún

doi:10.3390/ijms19113599

Abstract

Niemann–Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68—A marker of Kupffer cells in the liver—and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated.

Highlights

Niemann–Pick type C (NPC) is a fatal pediatric neurovisceral cholesterol storage disorder caused by loss of function mutations in the NPC1 or NPC2 genes
A recent study [4] reported the clinical features of 10 NPC patients who developed the disease in the newborn period between 1993 and 2015 and concluded that neonatal presentation is a rare form of NPC with exclusive visceral involvement in the newborn period and poor prognosis leading to premature death due to pulmonary complications and liver failure
No foam cells were found in wild-type (WT) mice, whereas increased staining was observed in NPC (Npc1−/−) tissues

Summary

Introduction

Niemann–Pick type C (NPC) is a fatal pediatric neurovisceral cholesterol storage disorder caused by loss of function mutations in the NPC1 or NPC2 genes. Both genes encode lysosomal proteins involved in the efflux of free cholesterol from lysosomes [1]. About 50% of classic NPC patients suffer from neonatal cholestasis, jaundice, and enlarged liver and/or spleen [5,6]. Of these patients, approximately 10% die from liver failure before they reach 6 months of age [7]

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