Diallyl disulfide alleviates hypercholesterolemia induced by a western diet by suppressing endoplasmic reticulum stress in apolipoprotein E-deficient mice

Abstract

Background: The endoplasmic reticulum (ER) plays a pivotal role in maintaining cellular metabolic homeostasis. ER stress refers to the accumulation of misfolded proteins, which can trigger an unfolded protein response for survival or death in the cells. Diallyl disulfide (DADS), a major active compound in garlic, has many health benefits for patients with metabolic diseases, especially cardiovascular or fatty liver diseases. However, its role in attenuating hypercholesterolemia by suppressing ER stress remains unknown. Therefore, in this study, we determined whether DADS supplementation could reduce ER stress in apolipoprotein E-deficient (ApoE−/−) mice fed a Western-type diet (WD). Methods: ApoE−/− mice were fed either a WD alone or a WD supplemented with 0.1% DADS for 12 weeks (n = 10). Levels of plasma total cholesterol, triglyceride, leptin, and insulin were determined. Western blotting was performed to measure protein levels involved in ER stress markers. Histology and Immunostaining were performed on aortic root sections to confirm the effect of DADS on histology and expression of ER chaperone protein GRP78. Results: The metabolic parameters showed that increases in fat weight, leptin resistance, and hypercholesterolemia were reversed in DADS-supplemented mice (p < 0.05). In addition, DADS ameliorated not only the protein of ER stress markers, phospho-eukaryotic initiation factor 2 subunit alpha and C/EBP homologous protein in the liver (p < 0.05) but also glucose-related protein 78 localization in the aorta. Conclusions: This indicates that DADS inhibits diet-induced hypercholesterolemia, at least in parts by regulating ER stress markers. DADS may be a good candidate for treating individuals with diet-induced hypercholesterolemia.