Mechanisms of Feedback Regulation of Vitamin A Metabolism

Abstract

Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.

Genetic hyperactivation of Nrf2 causes larval lethality in Keap1a and Keap1b-double-knockout zebrafish

“…The only downregulated pathways in keap1a;keap1b -DKO larvae that emerged in the current GO analysis were “vitamin A metabolic process” and “visual perception” pathways, to which the same genes belong, with no reduction in proinflammatory cytokine genes observed in Keap1 -knockdown mice [ 24 ]. Some genes in these pathways are known to be induced by retinoic acid [ 25 ], and it is possible that abnormally increased Nrf2 interacted with retinoic acid receptor α [ 26 ] and/or retinoid X receptor α [ 27 ] to inhibit transcriptional activation of their target genes. Interestingly, the expression of visual cycle genes such as lrata and rdh5 , which are downregulated in keap1a;keap1b -DKO larvae, is known to increase with age in mice [ 28 ].…”

Untargeted metabolomics analysis reveals dynamic changes in co-fermentation with human milk-derived probiotics and Poria cocos

“…Retinol is a dietary compound with vitamin A activity. Vitamin A is a key nutrient in the human diet, with particular importance in vision maintenance, embryonic development, immunity, tissue repair, and homeostasis ( O’Connor et al, 2022 ). Flavonoids are a large class of secondary metabolites with diverse structures and widely distributed in plants.…”

Retinoid metabolism: new insights

“…Presumably, because of the essential roles of vitamin A and because periods of nutrient limitation, including famines, have occurred throughout the course of history, ingested vitamin A is delivered, via chylomicrons (small particles of triglycerides, phospholipids, proteins, and cholesterol) to the liver for longer-term storage (Harrison 2005, Blaner et al 2016). In the liver, vitamin A is converted to retinyl esters (REs) by the enzyme lecithin:retinol acyl transferase (LRAT), primarily in the stellate cells, after vitamin A is transferred to these stellate cells from hepatocytes (Blomhoff et al 1984, Batten et al 2004, Wongsiriroj et al 2014, Saeed et al 2019, O'Connor et al 2022. These REs are stored for future use so that seasonal and other variations in dietary supplies do not prevent the target cell types that require vitamin A (most cell types in the body) from obtaining the vitamin A needed to carry out appropriate molecular activities.…”