Retinoic acid regulates pyruvate dehydrogenase kinase 4 (Pdk4) to modulate fuel utilization in the adult heart: Insights from wild-type and ß-carotene 9',10' oxygenase knockout mice.

Regulation of the pyruvate dehydrogenase (PDH) complex by the pyruvate dehydrogenase kinase PDK4 enables the heart to respond to fluctuations in energy demands and substrate availability. Retinoic acid, the transcriptionally active form of vitamin A, is known to be involved in the regulation of cardiac function and growth during embryogenesis as well as under pathological conditions. Whether retinoic acid also maintains cardiac health under physiological conditions is unknown. However, vitamin A status and intake of its carotenoid precursor ß-carotene have been linked to the prevention of heart diseases. Here, we provide in vitro and in vivo evidence that retinoic acid regulates cardiac Pdk4 expression and thus PDH activity. Furthermore, we show that mice lacking ß-carotene 9',10'-oxygenase (BCO2), the only enzyme of the adult heart that cleaves ß-carotene to generate retinoids (vitamin A and its derivatives), displayed cardiac retinoic acid insufficiency and impaired metabolic flexibility linked to a compromised PDK4/PDH pathway. These findings provide novel insights into the functions of retinoic acid in regulating energy metabolism in adult tissues, especially the heart.

ß-carotene improves fecal dysbiosis and intestinal dysfunctions in a mouse model of vitamin A deficiency.

Vitamin A deficiency (VAD) results in intestinal inflammation, increased redox stress and reactive oxygen species (ROS) levels, imbalanced inflammatory and immunomodulatory cytokines, compromised barrier function, and perturbations of the gut microbiome. To combat VAD dietary interventions with ß-carotene, the most abundant precursor of vitamin A, are recommended. However, the impact of ß-carotene on intestinal health during VAD has not been fully clarified, especially regarding the VAD-associated intestinal dysbiosis. Here we addressed this question by using Lrat-/-Rbp-/- (vitamin A deficient) mice deprived of dietary preformed vitamin A and supplemented with ß-carotene as the sole source of the vitamin, alongside with WT (vitamin A sufficient) mice. We found that dietary ß-carotene impacted intestinal vitamin A status, barrier integrity and inflammation in both WT and Lrat-/-Rbp-/- (vitamin A deficient) mice on the vitamin A-free diet. However, it did so to a greater extent under overt VAD. Dietary ß-carotene also modified the taxonomic profile of the fecal microbiome, but only under VAD. Given the similarity of the VAD-associated intestinal phenotypes with those of several other disorders of the gut, collectively known as Inflammatory Bowel Disease (IBD) Syndrome, these findings are broadly relevant to the effort of developing diet-based intervention strategies to ameliorate intestinal pathological conditions.