Inflammation rapidly modulates the expression of ALDH1A1 (RALDH1) and vimentin in the liver and hepatic macrophages of rats in vivo

BACKGROUND Members of the ALDH1 protein family, known as retinal dehydrogenases (RALDH), produce retinoic acid (RA), a metabolite of vitamin A, and may also oxidize other lipid aldehydes. Of three related ALDH1 genes, ALDH1A1 is most highly expressed in liver. ALDH1A1 is also rapidly gaining importance as a stem cell marker. We hypothesized that ALDH1A1 may have a broad cellular distribution in the liver, and that its expression may be regulated by RA and perturbed by inflammation. METHODS Studies were conducted in vitamin A-deficient and -adequate rats that were further treated with all-trans-RA or lipopolysaccharide (LPS) to induce a state of moderate inflammation. RALDH1A1 expression was determined by quantitative PCR and RALDH1, as well as marker gene expression, was determined by immunocytochemical methods. RESULTS Inflammation reduced ALDH1A1 mRNA in whole liver regardless of the level of vitamin A in the diet (P < 0.05), while treatment with RA reduced ALDH1A1 expression only in chow-fed rats. ALDH1A1 protein exhibited diffuse staining in hepatocytes, with greater intensity in the periportal region including surrounding bile ducts. Six h after administration of LPS, portal region macrophages were more numerous and some of these cells contained ALDH1A1. Vimentin, which was used as a marker for stellate cells and fibroblasts, was increased by LPS, P = 0.011 vs. without LPS, in both ED1 (CD68)-positive macrophages and fibroblastic stellate-like cells in the parenchyma as well as portal regions. Alpha-smooth muscle actin staining was intense around blood vessels, but did not change after LPS or RA, nor overlap with staining for vimentin. CONCLUSIONS Acute inflammation rapidly downregulates ALDH1A1 expression in whole liver while increasing its expression in periportal macrophages. Changes in ALDH1A1 expression appear to be part of the early acute-phase inflammatory response, which has been shown to alter the expression of other retinoid homeostatic genes. In addition, the rapid strong response of vimentin expression after treatment with LPS suggests that increased vimentin may be a useful marker of early hepatic inflammation.