β-Carotene Oxygenase 1 Activity Modulates Circulating Cholesterol Concentrations in Mice and Humans

Abstract

Background Plasma cholesterol is one of the strongest risk factors associated with the development of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction. Human studies suggest that elevated plasma β-carotene is associated with reductions in circulating cholesterol and the risk of myocardial infarction. The molecular mechanisms underlying these observations are unknown. Objective The objective of this study was to determine the impact of dietary β-carotene and the activity of β-carotene oxygenase 1 (BCO1), which is the enzyme responsible for the conversion of β-carotene to vitamin A, on circulating cholesterol concentration. Methods In our preclinical study, we compared the effects of a 10-d intervention with a diet containing 50 mg/kg of β-carotene on plasma cholesterol in 5-wk-old male and female C57 Black 6 wild-type and congenic BCO1-deficient mice. In our clinical study, we aimed to determine whether 5 common small nucleotide polymorphisms located in the BCO1 locus affected serum cholesterol concentrations in a population of young Mexican adults from the Universities of San Luis Potosí and Illinois: A Multidisciplinary Investigation on Genetics, Obesity, and Social-Environment (UP AMIGOS) cohort. Results Upon β-carotene feeding, Bco1−/− mice accumulated >20-fold greater plasma β-carotene and had ∼30 mg/dL increased circulating total cholesterol (P < 0.01) and non–HDL cholesterol (P < 0.01) than wild-type congenic mice. Our results in the UP AMIGOS cohort show that the rs6564851 allele of BCO1, which has been linked to BCO1 enzymatic activity, was associated with a reduction in 10 mg/dL total cholesterol concentrations (P = 0.009) when adjusted for vitamin A and carotenoid intakes. Non–HDL-cholesterol concentration was also reduced by 10 mg/dL when the data were adjusted for vitamin A and total carotenoid intakes (P = 0.002), or vitamin A and β-carotene intakes (P = 0.002). Conclusions Overall, our results in mice and young adults show that BCO1 activity impacts circulating cholesterol concentration, linking vitamin A formation with the risk of developing ASCVD.

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

“…In our clinical study, subjects carrying at least one copy of the BCO1 rs6564851-T allele, which increases BCO1 activity (40), showed a reduction in total serum cholesterol and non-HDL-C concentrations. Similarly, we observed that wild-type mice fed WD-β-carotene presented a decrease in total cholesterol and non-HDL-C concentrations in comparison to congenic Bco1 -/mice subjected to the same dietary regimen (10). These studies raised the question as to what mechanism underlies this association and whether these alterations in circulating cholesterol have a clinical significance.…”

“…We recently described an association between BCO1 activity and circulating cholesterol in mice and humans (10). In our clinical study, subjects carrying at least one copy of the BCO1 rs6564851-T allele, which increases BCO1 activity (40), showed a reduction in total serum cholesterol and non-HDL-C concentrations.…”

“…Interestingly, the binding site of ISX in the promoter region of the BCO1 gene coincides with the BCO1 rs6564851 allele (49). As we described in a recent paper, the BCO1 rs6564851 allele is associated with circulating cholesterol in humans (10). To determine if dietary vitamin A reduces intestinal cholesterol uptake by downregulating SR-BI or via other mechanisms, we measured the cholesterol absorption rate in Ldlr -/mice fed WD-VAD or WD-VA.…”

“…We recently showed that, in humans and mice, increased BCO1 activity is associated with a decrease in total plasma cholesterol and the cholesterol carried by the non-high-density lipoprotein fraction (non-HDL-C) (10). However, we did not examine whether the changes in plasma cholesterol affect the development of atherosclerosis.…”

Dietary β-Cryptoxanthin and α-Carotene Have Greater Apparent Bioavailability Than β-Carotene in Subjects from Countries with Different Dietary Patterns

“…Estimation of the bioavailability of dietary provitamin A carotenoids based on dietary intake data and concentrations in blood has several limitations, the most relevant probably being the disparity in the dietary intake assessment methods and FCT (referred to above), and the fact that it is impossible to estimate their conversion into retinol in the human intestine and other tissues. The extent of this conversion varies widely among individuals, depending on diverse host related factors, such as the vitamin A nutritional status, the nucleotide polymorphisms (SNPs) within the b-carotene 15,15 -monoxygenase and specific binding proteins involved in their metabolism, presence of disease, seasonal variation in the food intake, sex, age and body mass index [12,14,[75][76][77]. Strengths of this study include the homogeneous characteristics of the subjects in our four studies with respect to (normal) cholesterolemia and to (adequate) retinol nutritional status.…”