Metabolic Effects of Inflammation on Vitamin A and Carotenoids in Humans and Animal Models

Abstract

The association between inflammation and vitamin A (VA) metabolism and status assessment has been documented in multiple studies with animals and humans. The relation between inflammation and carotenoid status is less clear. Nonetheless, it is well known that carotenoids are associated with certain health benefits. Understanding these relations is key to improving health outcomes and mortality risk in infants and young children. Hyporetinolemia, i.e., low serum retinol concentrations, occurs during inflammation, and this can lead to the misdiagnosis of VA deficiency. On the other hand, inflammation causes impaired VA absorption and urinary losses that can precipitate VA deficiency in at-risk groups of children. Many epidemiologic studies have suggested that high dietary carotenoid intake and elevated plasma concentrations are correlated with a decreased risk of several chronic diseases; however, large-scale carotenoid supplementation trials have been unable to confirm the health benefits and in some cases resulted in controversial results. However, it has been documented that dietary carotenoids and retinoids play important roles in innate and acquired immunity and in the body's response to inflammation. Although animal models have been useful in investigating retinoid effects on developmental immunity, it is more challenging to tease out the effects of carotenoids because of differences in the absorption, kinetics, and metabolism between humans and animal models. The current understanding of the relations between inflammation and retinoid and carotenoid metabolism and status are the topics of this review.

Keywords: biomarkers; cytokines; infection; retinol; retinol-binding protein; sequestration; urinary loss.

FIGURE 1

The current understanding of the role of carotenoids in the mitigation of negative effects of ROS in response to insults. COX-2, cyclooxygenase 2; GPx, glutathione peroxidase; HO-1, heme oxygenase 1; IKK, IκB kinase; iNOS, inducible NO synthase; NQO1, NADPH quinone dehydrogenase 1; Nrf-2, nuclear factor (erythroid-derived 2)–like 2; RAS, proteins with intrinsic GTPase activity involved in cellular signal transduction; ROS, reactive oxygen species; SOD, superoxide dismutase. Reproduced from reference with permission.

FIGURE 2

Inflammation can negatively affect vitamin A balance through decreased dietary intake, reduced intestinal absorption, and increased urinary excretion. Inflammation may also cause the sequestration of vitamin A in the liver, which leads to hyporetinolemia. Reproduced from reference with permission.

FIGURE 3

Plasma retinol (A), RBP (B), and TTR (C) and liver RBP (D), RBP mRNA (E), and retinol (F) in control rats and in rats after the induction of inflammation by the administration of LPS. Data are means, n = 5. Results are for 24 h after the administration of LPS except for panel E, which represents results at 12 h. Data are from reference . *Different from C, P < 0.02. C, control group; RBP, retinol-binding protein; TTR, transthyretin.

FIGURE 4

The specific activity, calculated as the fraction of the dose divided by the plasma retinol concentration, in rat plasma during an insult with PBS (n = 2 for 3 and 7 d), LPS (n = 5 for 3 d), or recombinant human IL-6 (n = 5 for 7 d). The dashed line is the time that the insult was initially administered. The model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats. fdose; fraction of dose; ROHp; plasma retinol. This research was originally published in the Journal of Lipid Research (31). Gieng SH, Green MH, Green JB, Rosales FJ. Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats. J Lipid Res 2007;48:904–13. ©2007 the American Society for Biochemistry and Molecular Biology. Reproduced from reference with permission.

FIGURE 5

The current understanding of the relation of total liver reserves (expressed as μmol retinol/g liver) and the dynamic working range of the listed biomarker. Clinical signs of deficiency and depressed serum retinol concentrations occur during severe vitamin A depletion. Breastmilk retinol is a unique indicator for lactating women and can be extrapolated to infants. The dose-response tests offer more information on liver reserves than serum retinol concentrations alone. Isotope dilution is the only indirect biomarker that has utility along the entire continuum of reserves compared with a liver biopsy, which has limited feasibility but is considered the gold standard. Reproduced from reference with permission.

FIGURE 6

The impact of elevated acute-phase proteins on serum retinol concentrations in children (A). The curve on the far right reflects the distribution in children without inflammation. The middle curve reflects children who are in late convalescence (only AGP elevated), and the curve on the far left demonstrates serum retinol concentrations during early convalescence when both CRP and AGP are elevated. (B) The influence of adding an extra correction factor in the calculations for total liver retinol reserves in Zambian children with elevated CRP. If nonsymptomatic inflammation affects absorption, the relation would be the opposite; i.e., TLRs would be overestimated. Kernel density estimations produce a smoothed curve of data. AGP, α₁-acid glycoprotein; CRP, C-reactive protein; TLR, total liver reserve. Panel A is reproduced from reference with permission.