TY  - JOUR
A1  - Torres Núñez, Sandra
A1  - Solsona-Vilarrasa, Estel
A1  - Nuñez, Susana
A1  - Matías, Nuria
A1  - Insausti-Urkia, Naroa
A1  - Castro, Fernanda
A1  - Casasempere, Mireia
A1  - Fabriás, Gemma
A1  - Casas, Josefina
A1  - Enrich, Carlos
A1  - Fernández-Checa, José C.
A1  - Garcia-Ruiz, Carmen
T1  - Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation
T2  - Redox Biology
N2  - Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of mitochondrial cholesterol (mchol) content and impaired mitochondrial function and GSH depletion contribute to NPC disease. However, the underlying mechanism of mchol accumulation in NPC disease remains unknown. As STARD1 is crucial in intramitochondrial cholesterol trafficking and acid ceramidase (ACDase) has been shown to regulate STARD1, we explored the functional relationship between ACDase and STARD1 in NPC disease. Liver and brain of Npc1−/− mice presented a significant increase in mchol levels and STARD1 expression. U18666A, an amphiphilic sterol that inhibits lysosomal cholesterol efflux, increased mchol levels in hepatocytes from Stard1f/f mice but not Stard1ΔHep mice. We dissociate the induction of STARD1 expression from endoplasmic reticulum stress, and establish an inverse relationship between ACDase and STARD1 expression and LRH-1 levels. Hepatocytes from Npc1+/+ mice treated with U18666A exhibited increased mchol accumulation, STARD1 upregulation and decreased ACDase expression, effects that were reversed by cholesterol extraction with 2-hydroxypropyl-β-cyclodextrin. Moreover, transfection of fibroblasts from NPC patients with ACDase, decreased STARD1 expression and mchol accumulation, resulting in increased mitochondrial GSH levels, improved mitochondrial functional performance, decreased oxidative stress and protected NPC fibroblasts against oxidative stress-mediated cell death. Our results demonstrate a cholesterol-dependent inverse relationship between ACDase and STARD1 and provide a novel approach to target the accumulation of cholesterol in mitochondria in NPC disease.
KW  - Cholesterol
KW  - Acid ceramiase
KW  - Mitochondrial function
KW  - Oxidative stress
KW  - NPC disease
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63072
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-630725
SN  - 2213-2317
N1  - We acknowledge the support from grants SAF2017-85877R, PID2019-111669RB-100 and PID2020-115055RB-I00 from Plan Nacional de I+D funded by the Agencia Estatal de Investigacio ́n (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) and from the CIBER- EHD; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH; as well as support from AGAUR of the Generalitat de Catalunya SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Pro- spective European Drug-Induced Liver Injury Network, the “ER stress- mitochondrial cholesterol axis in obesity-associated insulin resistance and comorbidities”-Ayudas FUNDACION BBVA and the Red Nacional 2018-102799-T de Enfermedades Metabolicas y Cancer and the Project 201916/31 Contribution of mitochondrial oxysterol and bile acid metabolism to liver carcinogenesis 2019 by Fundacio ́ Marato TV3. E.S. V. was supported by a contract from the “Ministerio de Educacion, Cultura y Deporte” (FPU15/04537) of the Spanish Government.
VL  - 45
IS  - art. 102052
SP  - 1
EP  - 16
PB  - Elsevier
CY  - Amsterdam [u.a.]
ER  -