Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease.
Niemann-Pick type C (NPC) disease is a multisystem disorder resulting from mutations in the NPC1 gene that encodes a protein involved in intracellular cholesterol trafficking. Significant liver dysfunction is frequently seen in patients with this disease. The current studies used npc1 mutant mice to investigate the association between liver dysfunction and unesterified cholesterol accumulation, a hallmark of NPC disease. Data from 92 npc1(-/-) mice (age range, 9-56 days) revealed a significant positive correlation between the plasma activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and whole liver cholesterol content. In 56 day old npc1(-/-) mice that had been fed from 35 days of age a rodent diet or the same diet containing either cholesterol (1.0%, w/w) or ezetimibe (a sterol absorption inhibitor; 0.0125%, w/w), whole liver cholesterol content averaged 33.5 +/- 1.1, 87.9 +/- 1.7, and 20.8 +/- 0.9 mg, respectively. Again, plasma ALT and AST activities were positively correlated with hepatic cholesterol content. In contrast, plasma transaminase levels remained in the normal range in npc1(+/+) mice, in which hepatic esterified cholesterol content had been increased by 72-fold by feeding a high-cholesterol, high-fat diet. These studies suggest that the late endosomal/lysosomal content of unesterified cholesterol correlates with cell damage in NPC disease.
Beltroy
Eduardo P
EP
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887, USA.
Liu
Benny
B
Dietschy
John M
JM
Turley
Stephen D
SD
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death; D002784:Cholesterol / Q000032:analysis*; D011992:Endosomes / Q000737:chemistry; D022781:Hepatocytes / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008247:Lysosomes / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000473:pathology*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D002784:Cholesterol