β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

Abstract

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of cardiovascular diseases (CVDs), and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affect atherosclerosis progression in the atheroprone low-density lipoprotein receptor (LDLR) - deficient mice. In comparison to control-fed Ldlr-/- mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr-/-/Bco1-/- mice, despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

Vitamin A Deficiency during the Perinatal Period and First Weeks of Life Modifies Vitamin A and Lipid Postprandial Metabolism in Both Female and Male Young Rats

“…These data are consistent with a recent study showing that retinoic acid reduced hepatic lipoprotein secretion. [ 25 ] These data also confirm an alteration of lipid metabolism in rats as a symptom of vitamin A deficiency, in agreement with previous published data. [ 26,27 ] In particular, Oliveros and colleagues showed that vitamin A deficiency induced a hypolipidemic effect by decreasing both serum triglyceride and cholesterol levels in male rats.…”

Protective Effects of Individual and Combined Low Dose Beta-Carotene and Metformin Treatments against High-Fat Diet-Induced Responses in Mice

“…Dietary carotenoids, including BC and subcutaneously administered retinoids such as retinoic acid, ameliorate obesity and obesity development in animal models, and there is evidence of the same sense in humans [ 3 , 4 , 5 , 6 , 7 ]. Additionally, the beneficial effects of BC administration on blood glucose levels [ 8 ] and BC conversion into vitamin A on blood lipids and atherosclerosis progression [ 9 , 10 ] were described in pre-clinical studies.…”

All-trans-retinoic acid ameliorates atherosclerosis, promotes perivascular adipose tissue browning, and increases adiponectin production in Apo-E mice

“…In the current study, performed in the same animal model that consumption of a natural β-carotene enriched foods, composed of all-trans and 9-cis isomers, inhibited atherogenesis compared to the vitamin A deficiency diet, while vitamin A did not 39 . Recently, it has been shown that β-carotene and retinoic acid administration reduces the development of atherosclerosis, presumably by a reduction of the secretion of newly synthesized triglyceride and cholesteryl ester 40 . It has also been shown that 9-cis-RA stimulated macrophage cholesterol efflux and inhibited atherosclerotic plaque formation in Apo-E mice 41 .…”