Intracellular cholesterol accumulation and coenzyme Q10 deficiency in Familial Hypercholesterolemia

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2018-12, Vol.1864 (12), p.3697-3713
• Main Authors: Suárez-Rivero, Juan M., de la Mata, Mario, Pavón, Ana Delgado, Villanueva-Paz, Marina, Povea-Cabello, Suleva, Cotán, David, Álvarez-Córdoba, Mónica, Villalón-García, Irene, Ybot-González, Patricia, Salas, Joaquín J., Muñiz, Ovidio, Cordero, Mario D., Sánchez-Alcázar, José A.
• Format: Article
• Language: English
• Subjects: Cholesterol; Coenzyme Q10 deficiency; Familial Hypercholesterolemia; Inflammasome; LDL-R; Mitochondria dysfunction; Mitophagy
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2018.10.009

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. [Display omitted] •Fibroblasts from FH patients showed dysregulated mevalonate pathway, increased cholesterol levels and CoQ10 deficiency.•Secondary CoQ10 deficiency in FH fibroblasts was associated with mitochondrial depolarization and mitophagy activation.•Persistent mitophagy altered autophagy flux and induced inflammasome activation and increased production of cytokines.•Dysregulated mevalonate pathway in FH was corrected by CoQ10 treatment.