Retinol Status and Expression of Retinol-Related Proteins in Methionine-Choline Deficient Rats

Abstract

Vitamin A (retinol) plays an important role in vision and has pleiotropic functions in immune response, hematopoiesis, fertility, cell differentiation, growth, and morphogenesis (1). Both retinol deficiency and excessive doses of retinol cause malformations in the embryos of many vertebrate species, demonstrating that retinol plays an important role in embryogenesis. Retinoic acids, derivatives of retinol, act as the ligands of retinoic acid receptors (RAR) and retinoid X receptors (RXR), which are members of the nuclear receptor superfamily and are ligand-dependent transcriptional factors (2). RAR and RXR have subtypes (a, b, and g), and 9-cis retinoic acid (an isomer of retinoic acid) binds RARs and RXRs, whereas all-trans retinoic acid binds only RARs. Both types of retinoic acid receptors transcriptionally regulate the expression of target genes and exert multiple physiological functions.Dietary retinol has 2 major forms: retinyl esters derived from animal sources and provitamin A carotenoids, mainly in the form of b-carotene, derived from plants (3,4). Dietary retinyl esters are emulsified with fatty acids and bile salts and then micellized before hydrolysis in the lumen of the small intestine for retinol uptake. In the enterocytes, retinol is rapidly re-esterified with long-chain fatty acids. b-Carotene is absorbed in intestinal mucosal cells and then cleaved for retinal formation. b-Carotene 15,15′-monooxygenase (BCMO), the key enzyme of this process, cleaves b-carotene into 2 molecules of retinal, which are then esterified to retinyl ester in the intestine (4). Retinyl esters that are incorporated into chylomicrons are secreted from enterocytes and transferred to the liver through the lymphatic circulation. Chylomicrons containing retinyl esters are taken up by the liver and transferred to hepatic stellate cells (HSCs) for storage. Retinol in the liver is esterified by the enzyme lecithin:retinol acyltransferase (LRAT) to form retinyl esters. The transfer of retinol in the liver is mediated by cellular retinol binding protein (CRBP)-I, which delivers retinol to retinol binding protein (RBP) for secretion into the circulation. Retinoic acid levels are tightly regulated at the biosynthesis and oxidation stages (3). Retinol is reversibly oxidized to retinal by retinol dehydrogenases, and retinal is irreversibly oxidized to retinoic acid by members of the retinal dehydrogenase (ALDH) family. As mentioned above, the biological actions of retinoic acid isomers (all-trans and 9-cis forms) are conducted through their role as RAR and RXR ligands. Retinoic acids are oxidized by the cytochrome P450 26 family (CYP26A1, CYP26B1, and CYP26C1), following which their metabolites are conjugated with glucuronic acid.Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in developed countries, and Pediatrics, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Kita-ku, Sakai, Osaka 591-8025, Japan (Received October 9, 2013 Summary Retinol and its derivative, retinoic acid, have pleiotropic functions includ...

Dehydroepiandrosterone Alters Retinol Status and Expression of the β-Carotene 15,15′-Monooxygenase and Lecithin:Retinol Acyltransferase Genes

“…In the current study, BCMO expression in the testes of DHEA-fed rats was higher than in controls, which indicated opposite regulation to that in the liver and intestine. In previous studies, we reported that BCMO expression was higher in the testes of streptozotocininduced type 1 diabetic rats and methionine-cholinedefi cient NAFLD model rats, both of which had lower plasma retinol levels than the controls (16,17). These previous results are in agreement with the fi ndings of the current study, and suggest that the testes tissue of DHEA-treated rats might sense the need for retinol due to the reduced plasma retinol levels.…”

“…In comparison, Zucker rats with obesity and dyslipidemia showed lowered LRAT expression in the liver, which was associated with increased plasma retinol levels (20). These fi ndings suggest that altered LRAT expression may be associated with retinol status (16). In the current study, hepatic expression of the gene encoding LRAT is decreased by DHEA administration, which might lead to lowered retinol levels in the liver.…”

“…The gene encoding BMCO in rats is predominantly expressed in the liver and intestine, and weakly in the kidneys, testes, and lungs, which are target organs of retinoic acid as an active metabolite of retinol. The expression pattern of the BCMO gene in the liver and intestine varies in several diseases, including nephrosis, type 1 and type 2 diabetes, obesity with hyperlipidemia, and non-alcoholic fatty liver disease (NAFLD) (14,16,17,19,20). For instance, type 1 diabetic rats have lower retinol levels in the plasma and liver, and lower BCMO expression in the liver and intestine, than type 2 diabetic rats, which in comparison have higher plasma and hepatic retinol levels, and increased hepatic and intestinal BCMO expression (14,17).…”

“…titative real-time PCR was performed to determine the levels of mRNAs encoding BCMO, LRAT, glutathione peroxidase (GPx), CYP26A1, and ␤-actin in total RNA samples, as previously described (15)(16)(17). The genes encoding BCMO and ␤-actin were analyzed using the Master Hybridization Probe Kit, and the Master SYBR Green I Kit was used for analyzing the genes encoding LRAT, GPx, and CYP26A1.…”

Mechanisms of CCl₄-induced liver fibrosis with combined transcriptomic and proteomic analysis

“…Retinol and its derivative, retinoic acid, have critical roles in liver regeneration and pathogenesis including inflammation, steatosis, fibrosis, cirrhosis and cancer (Park et al, 2012). Retinol as well as cellular retinoic acid binding proteins and retinol-metabolizing enzymes are stored in HSCs (Miyazaki et al, 2014). During the fibrotic process, hepatic stellate cells are activated and lose their lipid drops which store retinol (de Paula et al, 2010).…”