Editing Vitamin A (section)

==Absorption, metabolism and excretion==
Retinyl esters from [[Animal source foods|animal-sourced foods]] (or synthesized for dietary supplements for humans and domesticated animals) are acted upon by retinyl ester hydrolases in the [[Lumen (anatomy)|lumen]] of the small intestine to release free retinol. Retinol enters [[enterocyte]]s by [[Passive transport|passive diffusion]]. Absorption efficiency is in the range of 70 to 90%. Humans are at risk for acute or chronic vitamin A toxicity because there are no mechanisms to suppress absorption or excrete the excess in urine.<ref name="DRI VitA"/> Within the cell, retinol is there bound to [[RBP2|retinol binding protein 2]] (RBP2). It is then enzymatically re-esterified by the action of [[lecithin retinol acyltransferase]] and incorporated into [[chylomicron]]s that are secreted into the [[lymphatic system]].

Unlike retinol, [[Β-Carotene|β-carotene]] is taken up by enterocytes by the membrane transporter protein [[SCARB1|scavenger receptor B1]] (SCARB1). The protein is upregulated in times of vitamin A deficiency. If vitamin A status is in the normal range, SCARB1 is downregulated, reducing absorption.<ref name=PKIN2020VitA/> Also downregulated is the [[enzyme]] [[beta-carotene 15,15'-dioxygenase]] (formerly known as beta-[[carotene]] 15,15'-monooxygenase) coded for by the BCMO1 gene, responsible for symmetrically cleaving β-carotene into retinal.<ref name=Wu2016/> Absorbed β-carotene is either incorporated as such into chylomicrons or first converted to retinal and then retinol, bound to RBP2. After a meal, roughly two-thirds of the chylomicrons are taken up by the liver with the remainder delivered to peripheral tissues. Peripheral tissues also can convert chylomicron β-carotene to retinol.<ref name="PKIN2020VitA"/><ref name="Chel2016">{{cite journal | vauthors = Chelstowska S, Widjaja-Adhi MA, Silvaroli JA, Golczak M | title = Molecular Basis for Vitamin A Uptake and Storage in Vertebrates | journal = Nutrients | volume = 8 | issue = 11 | page = 676 | date = October 2016 | pmid = 27792183 | pmc = 5133064 | doi = 10.3390/nu8110676 | doi-access = free | title-link = doi }}</ref>

The capacity to store retinol in the liver means that well-nourished humans can go months on a vitamin A deficient diet without manifesting signs and symptoms of deficiency. Two liver cell types are responsible for storage and release: [[hepatocyte]]s and [[hepatic stellate cell]]s (HSCs). Hepatocytes take up the lipid-rich chylomicrons, bind retinol to [[RBP4|retinol-binding protein 4]] (RBP4), and transfer the retinol-RBP4 to HSCs for storage in lipid droplets as retinyl esters. Mobilization reverses the process: retinyl ester hydrolase releases free retinol which is transferred to hepatocytes, bound to RBP4, and put into [[blood]] circulation. Other than either after a meal or when consumption of large amounts exceeds liver storage capacity, more than 95% of retinol in circulation is bound to RBP4.<ref name="Chel2016"/>

===Carnivores===
Strict [[carnivore]]s manage vitamin A differently than [[omnivore]]s and [[herbivore]]s. Carnivores are more tolerant of high intakes of retinol because those species have the ability to excrete retinol and retinyl esters in urine. Carnivores also have the ability to store more in the liver, due to a higher ratio of liver HSCs to hepatocytes compared to omnivores and herbivores. For humans, liver content can range from 20 to 30 μg/gram wet weight. Notoriously, [[polar bear]] liver is acutely toxic to humans because content has been reported in range of 2,215 to 10,400 μg/g wet weight.<ref name=Green2016>{{cite journal | vauthors = Green AS, Fascetti AJ | title = Meeting the Vitamin A Requirement: The Efficacy and Importance of ''β''-Carotene in Animal Species | journal = TheScientificWorldJournal | volume = 2016 | issue = | pages = 7393620 | date = 2016 | pmid = 27833936 | pmc = 5090096 | doi = 10.1155/2016/7393620 | doi-access = free | title-link = doi }}</ref> As noted, in humans, retinol circulates bound to RBP4. Carnivores maintain R-RBP4 within a tight range while also having retinyl esters in circulation. Bound retinol is delivered to cells while the esters are excreted in the urine.<ref name=Green2016/> In general, carnivore species are poor converters of ionone-containing carotenoids, and pure carnivores such as [[felidae]] (cats) lack the cleaving enzyme entirely. They must have retinol or retinyl esters in their diet.<ref name=Green2016/>

===Herbivores===
Herbivores consume ionone-containing carotenoids and convert those to retinal. Some species, including cattle and horses, have measurable amounts of β-carotene circulating in the blood, and stored in [[body fat]], creating yellow [[fat cell]]s. Most species have [[white fat]] and no β-carotene in circulation.<ref name=Green2016/>

===Activation and excretion===
In the liver and peripheral tissues of humans, retinol is reversibly converted to retinal by the action of alcohol dehydrogenases, which are also responsible for the conversion of [[ethanol]] to [[acetaldehyde]]. Retinal is irreversibly oxidized to retinoic acid (RA) by the action of aldehyde dehydrogenases. RA regulates the activation or deactivation of genes. The oxidative degradation of RA is induced by RA – its presence triggers its removal, making for a short-acting gene transcription signal. This deactivation is mediated by a [[cytochrome P450]] (CYP) enzyme system, specifically enzymes [[CYP26A1]], [[CYP26B1]] and [[CYP26C1]]. CYP26A1 is the predominant form in the human liver; all other human adult tissues contained higher levels of CYP26B1. CYP26C1 is expressed mainly during embryonic development. All three convert retinoic acid into 4-oxo-RA, 4-OH-RA and 18-OH-RA. [[Glucuronic acid]] forms water-soluble glucuronide conjugates with the oxidized metabolites, which are then excreted in urine and feces.<ref name="Kedish2016">{{cite book |vauthors=Kedishvili NY |title=The Biochemistry of Retinoid Signaling II |chapter=Retinoic Acid Synthesis and Degradation |series=Subcellular Biochemistry |volume=81 |pages=127–161 |date=2016 |pmid=27830503 |pmc=5551983 |doi=10.1007/978-94-024-0945-1_5 |isbn=978-94-024-0943-7 |chapter-url=}}</ref>