Beta-carotene Conversion to Vitamin A Delays Atherosclerosis Progression by Reducing Very-Low Density Lipoprotein Lipidation

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Medicine and Health Sciences


A positive association between beta-carotene (BC)-rich food intake and a reduction in metabolic disorder incidence, including heart disease, is prevalent in humans. Similarly, preclinical research finds dietary BC supplementation to reduce atherosclerosis progression. These beneficial outcomes are attributed to the antioxidant effects of BC and/or its role as retinoic acid precursor, which is produced by the activity of the enzyme beta-carotene oxygenase 1 (BCO1). To ascertain how BC reduces atherosclero-sis progression, and the mechanisms involved we utilized Ldlr-/- mice lacking the en-zyme BCO1 (Bco1-/-). BC-fed Ldlr-/- mice showed a significant reduction in plaque size when compared to control diet, which positively correlated with a decrease in plasma cholesterol and triglyceride levels (approximately 35% for both). These mice showed delayed atherosclerosis progression, determined by the total macrophage (CD68+ cells) and lipid content (ORO staining) in the plaque, which could not be explained by the effect of vitamin A in the intestinal cholesterol absorption, measured using the fecal dual-isotope ratio method. We also observed for the first time that in the absence of BCO1 (Ldlr-/-/Bco1-/- mice), the beneficial effects of BC on atherosclerosis were abro-gated, implicating vitamin A production in atherosclerosis, and discarding any role of the parent BC in this process. To elucidate the mechanism of action behind the effects of BC on atherosclerosis progression, we used radioisotope labeling techniques to perform lipoprotein production assays in hepatocytes exposed to retinoic acid, the active metabolite derived from BC. We show that retinoic acid decreases VLDL cholester-ol and triglyceride lipidation (approximately 25% for both) without affecting VLDL particle number. Similarly, a single dose of retinoic acid was sufficient to reproduce the effects observed in cell culture, unveiling retinoic acid and its precursor BC as important modulators of VLDL secretion. Overall here we demonstrate that BC, a retinoic acid precursor in mammals, reduces atherosclerosis progression by reducing hepatic lipoprotein secretion, providing a mechanistic explanation to the positive effects of BC intake in humans.


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