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

Felix Zhou,Xiaoyun Wu,Ivan Pinos,Benjamin M Abraham,Tessa J Barrett,Johannes Von Lintig,Edward A Fisher,Jaume Amengual

doi:10.1194/jlr.ra120001066

Abstract

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of 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 affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with 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.

Highlights

Supplementary key words retinoids retinoic acid cholesterol very low density lipoprotein carotenoids foam cells carotenoid oxygenases low density lipoprotein-cholesterol liver precursor of vitamin A and its metabolite retinoic acid, a potent nuclear receptor activator involved in the regulation of lipid metabolism and antiinflammatory macrophage polarization [7]
Plaque area correlated with reduced plasma cholesterol in Ldlr / mice (Fig. 2), and mice fed WD providing IU retinyl acetate/g (WD-VA) showed similar results on plasma cholesterol compared with those fed WD- carotene (Fig. 3A)
Ldlr / /Bco1 / mice fed WD -carotene, which cannot convert -carotene to VA, do not show significant differences either on atherosclerosis progression or plasma cholesterol compared with those fed WD-VAD (Fig. 2)

Summary

Introduction

Rodents do not accumulate -carotene in tissues, which limits the feasibility of studying whether intact -carotene performs a biological activity other than VA production. Several years ago we characterized BCO1-deficient mice, which overcome this limitation; when fed -carotene, Bco1 / mice accumulate -carotene in tissues and plasma, as it occurs in humans [9]. We did not examine whether the changes in plasma cholesterol affect the development of atherosclerosis. We crossed Bco1 / mice with Ldlr / mice to examine whether intact -carotene or its vitamin A metabolites affect atherosclerosis progression and, if so, the molecular mechanisms underlying these effects. Utilizing cell- culture studies and animal models, we studied the mechanisms by which -carotene and VA regulate plasma cholesterol concentration and whether the specific ablation of BCO1 in myeloid cells affects atherosclerosis development.

Methods

Results

Conclusion