Eat Your Carrots! β-Carotene and Cholesterol Homeostasis (2024)

See corresponding article on page 2023.

Some might be surprised that cholesterol and β-carotene, the eponymous representative of the substance class of carotenoids, have a great deal in common. Both compounds are isoprenoids, meaning their carbon skeletons are synthesized by condensation of a distinct number of isoprene (C5) units. Their transport in our body is facilitated by the same lipoprotein classes, and their cellular uptake is mediated by the same scavenger receptors (1, 2). Moreover, both lipids are precursors for hormone-like metabolites, which bind to ligand-activated transcription factors that belong to the superfamily of nuclear hormone receptors (3). Despite these considerable overlapping properties, there are also significant differences between these 2 lipids. The consumption of β-carotene-rich food is generally regarded as healthy, whereas cholesterol-rich food is decried. The latter food may increase cholesterol plasma concentrations and the risk of developing atherosclerotic cardiovascular disease (ASCVD). Elevated cholesterol is associated with the abnormal accumulation of apolipoprotein B100–containing lipoproteins within the arterial wall. These lipoproteins are retained within the subendothelial space of the arterial walls and can promote inflammatory responses that eventually lead to the development and growth of atherosclerotic lesions. Rupture of these lesions can cause thrombosis and arterial occlusion, leading to myocardial infarction and stroke, the most prevalent cause of death in the United States.

β-Carotene also is present in atherosclerotic lesions and contributes to the yellowish color of these pathologic structures. However, in contrast to cholesterol, elevated plasma concentrations of β-carotene are inversely associated with the incidence of ASCVD (4). To date, there are limited molecular explanations for this inverse association, although the assumption that consumption of carotenoid-rich food such as fruit and vegetables has health benefits is widely accepted by the public.

The study by Amengual et al. (5) published in this issue of the Journal of Nutrition sheds new light onto the putative interaction between β-carotene and cholesterol metabolism and is a potential gamechanger. To investigate the putative effects of dietary β-carotene on cholesterol homeostasis, the researchers used the β-carotene-oxygenase-1 (BCO1) knockout mice in their preclinical study (6). This mouse mutant cannot convert β-carotene into retinoids (vitamin A and its metabolites) by oxidative cleavage of the C15, C15′ double bond, and similar to humans, it accumulates significant amounts of β-carotene in blood and tissues. After a 10-d dietary intervention on a Western-style diet, rich in cholesterol and supplemented with β-carotene (approximately the amount present in carrots and pumpkins), the Bco1knockout mice displayed significantly elevated plasma concentrations of β-carotene. The congenic wild-type mice readily converted absorbed β-carotene to retinoids. Surprisingly, β-carotene accumulation was associated with a significant increase of plasma cholesterol concentrations compared with that of wild-type controls. The observed change in cholesterol concentrations exclusively affected the non-HDL cholesterol fraction, which is known colloquially as “bad cholesterol.”

What initially surprises becomes more evident upon closer inspection. Previously, it was assumed that effects of β-carotene on cholesterol metabolism are related to the antioxidant properties of the nutrient (e.g., as free radical scavengers in lipophilic environments such as membranes and lipoproteins) (7). The finding by Amengual et al. (5) pointed toward a different direction—namely, its function as a provitamin. BCO1 catalytically converts β-carotene to 2 molecules of all-trans-retinal. All-trans-retinal is the direct metabolic precursor of all-trans-retinoic acid, a potent and dominant modulator of lipid metabolism and immunity (Figure 1). Dyslipidemia and inflammation are hallmarks of the etiology of ASCVD. All-trans-retinoic acid, via retinoic acid and retinoid X receptors, can regulate, among other processes, the expression of genes that affect hepatic lipid homeostasis and immune cell differentiation and function (8, 9). Studies in mice have already revealed that the effects of β-carotene on adiposity and immunity depend on BCO1 (10, 11). Thus, the pigment's cholesterol-lowering effect may be mediated by a comparable mechanism.

The human BCO1 gene displays single base pair polymorphisms (SNPs) that affect plasma concentrations of β-carotene and other carotenoids (12). In addition, vitamin A status regulates BCO1 activity via a negative feedback loop mediated by the intestine-specific homeobox (ISX) transcription factor (13). As a consequence, intestinal enterocytes cease the expression of the BCO1 gene and diminish the production of retinoids when the body's vitamin A stores are filled.

Amengual et al. (5) next associated known SNPs within the BCO1 gene with cholesterol plasma concentrations in the Universities of San Luis Potosi and Illinois: A Multidisciplinary Investigation on Genetics, Obesity, and Social Environment (UP AMIGOS) cohort, a group of college applicants of Mexican ethnicity. A strong association was found for SNP rs6564851, which is located upstream of the BCO1 gene coding region on chromosome 16. Carriers of at least 1 copy of the T-allele of the SNP exhibited a significant 10% reduction of total cholesterol and also of non-HDL cholesterol. The SNP had been previously identified by a genomewide association study in an Italian cohort, and the association of the SNP with plasma β-carotene concentrations was replicated in the Women's Health and Aging Study and in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (14). A small clinical study conducted with Caucasian female volunteers showed that the SNP has a direct impact on BCO1 activity in the intestine, as determined by the retinyl ester to β-carotene ratio in the postprandial triglyceride-rich lipoprotein fraction after a β-carotene-rich meal (15). The DNA region surrounding the SNP contains several transcription factor binding sites, including a putative binding site for ISX that may affect BCO1 gene expression in the intestine and thus the β-carotene conversion rate into retinoids (13). Therefore, Amengual et al. (5) concluded that the BCO1 genotype is associated with cholesterol plasma concentrations in the UP AMIGOS cohort, thereby corroborating their preclinical results in the BCO1-deficient mouse model (5).

In the future, it will be important to replicate the clinical study in larger cohorts. However, the association between the non-HDL cholesterol concentrations and BCO1 genotype in the UP AMIGOS cohort is remarkable. Participants of the study cohort are young and had relatively low dietary β-carotene intake. Although speculative, it might be predictable that the observed effect increases with age and that the cholesterol-lowering effect of β-carotene is enhanced on diets rich in carotenoids. Notably, previous studies linked low vitamin A blood concentrations to coronary events such as myocardial infarction (16). β-Carotene is a major source of vitamin A, but as recently noted by a conference elucidating the current status of the β-carotene research field, dietary intake is below recommended concentrations of <3mg/d in many populations (17). The trend toward insufficient β-carotene/vitamin A intake is becoming even more evident with vegetarian and vegan lifestyles.

Taken together, the study by Amengual et al. (5) sheds new light on the cholesterol research field by linking diet, BCO1 genetics, and ASCVD. It will be fascinating to clarify how β-carotene and BCO1 affect cholesterol metabolism. Is the effect of β-carotene mainly caused by an improved vitamin A status? Does the effect of β-carotene involve canonical retinoid signaling and/or other mechanisms? Which particular step in cholesterol metabolism is influenced by β-carotene? Does genetic variability in the BCO1 gene associate with ASCVD, and is there a need for personalized intake recommendations based on genetic prediction? Further exploration into these topics will eventually define molecular underpinnings of the regulation of cholesterol concentrations by β-carotene and its retinoid metabolites. An improved understanding of the physiologic action of β-carotene will aid in the development of nutritional intervention strategies to prevent chronic disease states.