Intracellular cholesterol accumulation and coenzyme Q10 deficiency in Familial Hypercholesterolemia

Publication date: Available online 5 October 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Juan M. Suárez-Rivero, Mario de la Mata, Ana Delgado Pavón, Marina Villanueva-Paz, Suleva Povea-Cabello, David Cotán, Mónica Álvarez-Córdoba, Irene Villalón-García, Patricia Ybot-González, Joaquín J. Salas, Ovidio Muñiz, Mario D. Cordero, José A. Sánchez-AlcázarAbstractFamilial 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 supplemen...

Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - October 5, 2018 Category: Molecular Biology Source Type: research