Retinoic acid

ATRA = All-trans-retinoic acid.

ATRA down-regulates CBS and BHMT

Apparently ATRA down-regulates CBS and BHMT enzymes:

These results demonstrate that ATRA intensifies ER stress and induces apoptosis in GnT-V-AS/7721 cells by disturbing homocysteine metabolism through the down-regulation of CBS and BHMT, depleting the cellular GSH and, in turn, altering the cellular redox status. (R1)

ATRA induces GNMT and MS (MTR)

A significant increase (105%) in GNMT activity was observed with doses as low as 5 μmol/kg body weight, whereas maximal induction (231%) of GNMT activity was achieved at 30 μmol/kg body weight. Induction of hepatic GNMT by ATRA was rapid, exhibiting a 31% increase after a single dose (1 d) and achieving maximal induction (95%) after 4 d. Plasma methionine and homocysteine concentrations were decreased 42 and 53%, respectively, in ATRA-treated rats compared with controls.

In support of this finding, the hepatic activity of methionine synthase, the folate-dependent enzyme required for homocysteine remethylation, was elevated 40% in ATRA-treated rats. This work demonstrates that ATRA administration exerts a rapid effect on hepatic methyl group, folate and homocysteine metabolism at doses that are within the therapeutic range used by humans. (R2)

Vitamin A treatment increases the production of erythropoietin

Erythropoietin (EPO) is a stimulant of erythropoiesis (red blood cell synthesis).

Results: At baseline, 54% of children were anemic; 77% had low vitamin A status. In the vitamin A group at 10 mo, serum retinol improved significantly compared with the control group (P < 0.02).

Vitamin A treatment increased mean hemoglobin by 7 g/L (P < 0.02) and reduced the prevalence of anemia from 54% to 38% (P < 0.01).

Vitamin A treatment increased mean corpuscular volume (P < 0.001) and decreased serum transferrin receptor (P < 0.001), indicating improved iron-deficient erythropoiesis.

Vitamin A decreased serum ferritin (P < 0.02), suggesting mobilization of hepatic iron stores.

Calculated from the ratio of transferrin receptor to serum ferritin, overall body iron stores remained unchanged. In the vitamin A group at 10 mo, we observed an increase in EPO (P < 0.05) and a decrease in the slope of the regression line of log10(EPO) on hemoglobin (P < 0.01). (R3)

Vitamin A downregulates Hepcidin

Recent studies suggest that vitamin A modulates the levels of Hamp messenger RNA (mRNA), which encodes the hepcidin hormone, an antimicrobial peptide that regulates systemic iron homeostasis. This hormone binds to ferroportin (FPN1), an iron exporter protein located on the cell surface, triggering its internalization, ubiquitination and subsequent lysosomal degradation, thereby preventing iron release from enterocytes and splenic macrophages.

Thus, hepcidin orchestrates systemic iron homeostasis by reducing intestinal iron absorption and iron recycling from senescent red blood cells in the reticuloendothelial cells. (R4)

Differences between Iron deficiency and Vitamin A deficiency anemias

Fe deficiency anemia, which develops in a series of steps starting with the depletion of Fe stores, is identified by a

• reduction in serum Fe
• an increase in total iron binding capacity (TIBC) and transferrin receptors
• low transferrin saturation
• reduced serum ferritin
• low mean corpuscular volume (MCV)
• low mean corpuscular hemoglobin (MCH).

In contrast, VAD anemia is associated with

• **reduction in serum Fe
• low TIBC
• low transferrin saturation
• increased serum ferritin concentration** (due to a lower mobilization of Fe stores, with increased deposition of Fe in the liver and spleen). (R5)

Synergistic role with Lithium

Lithium inhibits proteasome, which prevents RARA from degradation:

LiCl interacts synergistically with all-trans-retinoic acid, promoting the terminal differentiation of WEHI-3B D(+) cells, a phenomenon partially due to the ability of the monovalent lithium cation to inhibit the proteasome-dependent degradation of retinoic acid receptor alpha protein. (R6)