RT Journal Article
T1 Intracellular cholesterol accumulation and coenzyme Q10 deficiency in Familial Hypercholesterolemia.
A1 Suárez-Rivero, Juan M
A1 de la Mata, Mario
A1 Pavón, Ana Delgado
A1 Villanueva-Paz, Marina
A1 Povea-Cabello, Suleva
A1 Cotán, David
A1 Álvarez-Córdoba, Mónica
A1 Villalón-García, Irene
A1 Ybot-González, Patricia
A1 Salas, Joaquín J
A1 Muñiz, Ovidio
A1 Cordero, Mario D
A1 Sánchez-Alcázar, José A
K1 Cholesterol
K1 Coenzyme Q(10) deficiency
K1 Familial Hypercholesterolemia
K1 Inflammasome
K1 LDL-R
K1 Mitochondria dysfunction
K1 Mitophagy
AB Familial Hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and increased risk for premature cardiovascular disease. Here, we examined FH pathophysiology in skin fibroblasts derived from FH patients harboring heterozygous mutations in the LDL-receptor. Fibroblasts from FH patients showed a reduced LDL-uptake associated with increased intracellular cholesterol levels and coenzyme Q10 (CoQ10) deficiency, suggesting dysregulation of the mevalonate pathway. Secondary CoQ10 deficiency was associated with mitochondrial depolarization and mitophagy activation in FH fibroblasts. Persistent mitophagy altered autophagy flux and induced inflammasome activation accompanied by increased production of cytokines by mutant cells. All the pathological alterations in FH fibroblasts were also reproduced in a human endothelial cell line by LDL-receptor gene silencing. Both increased intracellular cholesterol and mitochondrial dysfunction in FH fibroblasts were partially restored by CoQ10 supplementation. Dysregulated mevalonate pathway in FH, including increased expression of cholesterogenic enzymes and decreased expression of CoQ10 biosynthetic enzymes, was also corrected by CoQ10 treatment. Reduced CoQ10 content and mitochondrial dysfunction may play an important role in the pathophysiology of early atherosclerosis in FH. The diagnosis of CoQ10 deficiency and mitochondrial impairment in FH patients may also be important to establish early treatment with CoQ10.
YR 2018
FD 2018-10-05
LK http://hdl.handle.net/10668/13036
UL http://hdl.handle.net/10668/13036
LA en
DS RISalud
RD Apr 6, 2025