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Title

Intracellular cholesterol accumulation and coenzyme Q10 deficiency in Familial Hypercholesterolemia

AuthorsSuarez-Rivero, Juan M.; Mata, Mario de la ; Delgado Pavón, Ana; Villanueva Paz, Marina; Povea-Cabello, Suleva; Cotán, David ; Álvarez-Córdoba, Mónica; Villalón-García, Irene; Ybot, Patricia; Salas, Joaquín J. ; Muñiz, Ovidio; Cordero, Mario de; Sánchez-Alcázar, José Antonio
KeywordsFamilial Hypercholesterolemia
LDL-R
Cholesterol
Coenzyme Q10 deficiency
Mitochondria dysfunction
Inflammasome
Mitophagy
Issue DateDec-2018
PublisherElsevier
CitationBiochimica et Biophysica Acta - Molecular Basis of Disease 1864 (12): 3697-3713 (2018)
AbstractFamilial 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.
Description63 Páginas; 8 Figiras; 9 Figuras suplementarias
Publisher version (URL)http://dx.doi.org/10.1016/j.bbadis.2018.10.009
URIhttp://hdl.handle.net/10261/171404
ISSN0925-4439
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