Lack of Annexin A6 exacerbates liver dysfunction and reduces lifespan of NPC1- deficient mice
Date
2020
Type:
Article
item.page.extent
item.page.accessRights
item.contributor.advisor
ORCID:
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier Inc./ American Society for Investigative Pathology
item.page.isbn
item.page.issn
item.page.issne
item.page.doiurl
item.page.other
item.page.references
Abstract
Niemann-Pick type C disease (NP-C) is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NP-C disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NP-C disease is common. Recently, we demonstrated that the depletion of annexin A6 (ANXA6), which is most abundant in the liver and involved in cholesterol transport, ameliorated cholesterol accumulation in Npc1 mutant cells. To evaluate the potential contribution of ANXA6 in the progression of NP-C disease, double-knockout mice (Npc1-/-/Anxa6-/-) were generated and examined for lifespan, neurological and hepatic functions, as well as liver histology and ultrastructure. Strikingly, lack of ANXA6 in NPC1-deficient animals did not prevent the cerebellar degeneration phenotype but further deteriorated their compromised hepatic functions and reduced lifespan. Moreover, livers of Npc1-/-/Anxa6-/- mice contained a significantly elevated number of foam cells congesting the sinusoidal space, a feature commonly associated with inflammation. We hypothesize that ANXA6 deficiency in Npc1-/- mice do not reverse neurological and motor dysfunction and it further worsens overall liver function, exacerbating hepatic failure in NP-C disease.
Description
Centro de Genética y Genómica
item.page.coverage.spatial
item.page.sponsorship
Citation
Meneses-Salas E, Garcia-Forn M, Castany-Pladevall C, Lu A, Fajardo A, Jose J, Wahba M, Bosch M, Pol A, Tebar F, Klein AD, Zanlungo S, Pérez-Navarro E, Grewal T, Enrich C, Rentero C, Lack of Annexin A6 exacerbates liver dysfunction and reduces lifespan of NPC1-deficient mice, The American Journal of Pathology (2021)
Keywords
Liver dysfunction, Lifespan, Annexin A6