Lack of Annexin A6 exacerbates liver dysfunction and reduces lifespan of Niemann-Pick Type C protein–deficient mice

Elsa Meneses-Salas, Marta Garcia-Forn, Carla Castany-Pladevall, Albert Lu, Alba Fajardo, Jaimy Jose, Mohamed Wahba, Marta Bosch, Albert Pol, Francesc Tebar, Andres D Klein, Silvana Zanlungo, Esther Pérez-Navarro, Thomas Grewal, Carlos Enrich, Carles Rentero

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2 Citations (Scopus)
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Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NPC disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NPC disease is common. Recently, we found 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 NPC disease, double-knockout mice (Npc1−/−/Anxa6−/−) were generated and examined for lifespan, neurologic and hepatic functions, as well as liver histology and ultrastructure. Interestingly, lack of ANXA6 in NPC1-deficient animals did not prevent the cerebellar degeneration phenotype, but further deteriorated their compromised hepatic functions and reduced their 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 not only does not reverse neurologic and motor dysfunction, but further worsens overall liver function, exacerbating hepatic failure in NPC disease.

Original languageEnglish
Pages (from-to)475-486
Number of pages12
JournalAmerican Journal of Pathology
Issue number3
Publication statusPublished - Mar 2021


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