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Biochemical, Molecular, and Genetic Mechanisms

Red Grape Juice Polyphenols Alter Cholesterol Homeostasis and Increase LDL-Receptor Activity in Human Cells In Vitro^1,2

Alberto Dávalos^*, Carlos Fernández-Hernando^*,3, Francisca Cerrato^*, Javier Martínez-Botas^*, Diego Gómez-Coronado^*, Carmen Gómez-Cordovés and Miguel A. Lasunción^*,**,4

^* Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Madrid, Spain; Instituto de Fermentaciones Industriales, CSIC, Madrid, Spain; and ^** Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Madrid, Spain

⁴ To whom correspondence should be addressed. E-mail: miguel.a.lasuncion{at}hrc.es.

Red grape juice (RGJ) polyphenols have been shown to reduce circulating levels of LDL cholesterol and to increase LDL receptor activity. To explore the effect of RGJ-derived polyphenols on intracellular cholesterol homeostasis, human hepatocarcinoma HepG2 and promyelocytic HL-60 cell lines were incubated in serum-free medium, with or without LDL, in the presence or absence of RGJ. In the presence of LDL, RGJ increased both the activity and cell surface expression of the LDL receptor, and increased the cell total cholesterol content. In cells exposed to LDL, RGJ also increased levels of the active form of sterol regulatory element-binding protein-1 and mRNA expression of the LDL receptor and hydroxymethylglutaryl-CoA reductase. In contrast, RGJ caused a marked reduction in the expression of CYP7A1, apolipoprotein B, ABCA1, and ABCG5. Experiments using the acyl-CoA cholesterol acyltransferase inhibitor S-58035 indicated that no measurable free cholesterol from endocytosed LDL reaches the endoplasmic reticulum in cells treated with RGJ. Finally, fluorescence microscopy revealed that in RGJ-treated cells, DiI-labeled LDL did not colocalize with CD63, a protein localized at steady state in the internal vesicles of late endosomes. These results indicate that RGJ polyphenols disrupt or delay LDL trafficking through the endocytic pathway, thus preventing LDL cholesterol from exerting regulatory effects on intracellular lipid homeostasis.

KEY WORDS: • LDL receptor • red grape juice polyphenols • cholesterol trafficking • LDL cholesterol

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