Intracellular cholesterol accumulation and coenzyme Q10 deficiency in Familial Hypercholesterolemia

Autor: Irene Villalón-García, Mónica Álvarez-Córdoba, Ana Delgado Pavón, Suleva Povea-Cabello, David Cotán, Mario D. Cordero, Patricia Ybot-Gonzalez, Joaquín J. Salas, Juan M. Suárez-Rivero, Marina Villanueva-Paz, Mario de la Mata, Ovidio Muñiz, José Antonio Sánchez-Alcázar
Přispěvatelé: Instituto de Salud Carlos III, European Commission, Asociación de Enfermos de Patologías Mitocondriales (España), Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro (España)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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Popis: 63 Páginas; 8 Figiras; 9 Figuras suplementarias
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.
This work was supported by the Instituto de Salud Carlos III, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea) under Grant PI16/00786, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro). We thank Dr. Juan Bautista Lorite for his support throughout the study. In memoriam of José Villar Ortiz, Director de la Unidad de Lípidos del Hospital Universitario Virgen del Rocío de Sevilla.
Databáze: OpenAIRE
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