Fig 1.
Intracellular metabolism of retinol (vitamin A) in the liver.
Retinol is provided by our diet and transported via chylomicrons into the liver, where it is bound to retinol binding protein (RBP). Retinol is converted to retinyl ester by lecithin retinol acyltransferase (LRAT), for storage. Retinol is converted into all-trans-retinal in the liver via two oxidative steps. The first enzymatic step is the reversible oxidation of retinol to retinal by three types of enzymes: i) members of retinal dehydrogenase family (RDH5, RDH10, RDH11), ii) alcohol dehydrogenase (ADH1, ADH1B and ADH1C); and iii) membrane-bound short-chain dehydrogenases/reductases (DHRS3 and DHRS4), all involved in maintaining an equilibrium between retinal and retinol. The second and irreversible step is the oxidation of retinal to all-trans-retinoic acid by retinaldehyde dehydrogenase 1 family, member A1, A2 and A3 (ALDH1A1, ALDH1A2 and ALDH1A3). Excessive all-trans-retinoic acid, which is bound to cellular retinoic acid-binding proteins (CRABP1 and CRABP2), is not recycled back to retinol and must be oxidized to be eliminated from the body by the cytochrome P450 family members CYP26A1 and CYP26B1. Newly synthesized all-trans-retinoic acid can be bound to CRABP2. All-trans-retinoic acid that enters the nucleus, binds to a retinoic acid receptor/retinoic X receptor (RAR/RXR) heterodimer and stimulates transcription of target genes. The plus sign (+) indicates increased expression of the enzyme AKR1B10, whereas the minus sign (-) indicates a reduced expression of the enzymes ALDH1A2 and ALDH1A3.
Table 1.
Clinical and biochemical parameters in liver donors and patients with simple steatosis and non-alcoholic steatohepatitis.
Fig 2.
Plasma retinol levels in liver donors and patients with simple steatosis and non-alcoholic steatohepatitis.
LD: liver donors, SS: simple steatosis, NASH: non-alcoholic steatohepatitis, NAFLD: non-alcoholic fatty liver disease (SS: simple steatosis + NASH: non-alcoholic steatohepatitis). A p<0.05, based on ANOVA with Tukey´s post-hoc test.
Fig 3.
Genes related to retinol metabolism that were differentially expressed among liver donors and patients with simple steatosis or non-alcoholic steatohepatitis.
Included are genes with a corrected post-hoc p-value <0.05. Gene expression levels are given as fold-changes between two groups. LD: liver donors, SS: simple steatosis, NASH: non-alcoholic steatohepatitis.
Fig 4.
Principal component analysis including 10 genes related to retinol metabolism that were differentially expressed between patients with simple steatosis or non-alcoholic steatohepatitis and liver donors.
(LD, closed circle; SS, closed square; NASH, closed triangle). Panel A shows the first two principal components extracted (PC1 and PC2). The location of each patient in the graph (PC1 versus PC2) separates patients with NAFLD (SS and NASH) from the LD group. This means that NAFLD patients have a distinct gene expression profile for retinol metabolism related genes compared to LD. In Panel B, eigenvectors are presented for PC1 and PC2. The 10 selected genes contributed similarly to PC1, except RXRB andRDH10 that had slightly lower eigenvector values. For PC2, RXRB, RDH10, ADH1B and AKR1B10 had the highest eigenvalues. Panel C shows the Spearman correlation between PC1 (separating NAFLD and LD) and retinol levels for all three groups combined. The analysis was repeated separately for patients and controls. In this case the correlation was only significant for NAFLD (rho = 0.480, p = 0.005) but not for LD.
Table 2.
Food dietary intake in liver donors and patients with simple steatosis and non-alcoholic steatohepatitis.