title: Recovery from liver disease in a Niemann-Pick type C mouse model.
abstract: Loss of function of Niemann-Pick C1 (NPC1) leads to lysosomal free cholesterol storage, resulting in the neurodegenerative disease Niemann-Pick disease type C (NPC). Significant numbers of patients with NPC also suffer from liver disease. Currently, no treatments exist that alter patient outcome, and it is unknown if recovery from tissue damage can occur even if a treatment were found. Our laboratory developed a strategy to test whether mice can recover from NPC liver disease. We used antisense oligonucleotides to knock down hepatic expression of NPC1 in BALB/C mice for either 9 or 15 weeks. This recapitulated liver disease with hepatomegaly, cell death, and fibrosis. Then, antisense oligonucleotide treatment was halted for an additional 4, 9, or 15 weeks. We report that significant liver recovery occurred even when NPC1 protein expression only partially returned to normal. Several pathological phenotypes were alleviated, including hepatomegaly, cholesterol storage, and liver cell death. Histological examination revealed that foamy cell accumulation was relieved; however, liver fibrosis increased. Additionally, resolution of cholesterol storage and liver cell death took longer in mice with long-term knockdown. Finally, we found that transcription of cholesterol homeostatic genes was significantly disrupted during the recovery phase after long-term knockdown.
authors.affiliation: Department of Physiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Sayre
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Rimkunas
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.forename: Laura
authors.initials: L
authors.lastname: Liscum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006529:Hepatomegaly / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics; D008107:Liver Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000150:complications*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D016376:Oligonucleotides, Antisense; D011506:Proteins; D002784:Cholesterol