Dexamethasone modulates α2-macroglobulin and apolipoprotein E gene expression in cultured rat liver fat-storing (Ito) cells

Abstract

Fat-storing (Ito) cells are perisinusoidal liver cells thought to play a central role in vitamin A metabolism and fibrongenesis. Glucocorticoids have been shown to be beneficial in the treatment of certain types of liver diseases by delaying the development of cirrhosis. To study the regulatory effects of dexamethasone on Ito cell gene expression, Ito cells were isolated from normal rat liver and primary cultures were established. The effect of dexamethasone on the synthesis of alpha 2-macroglobulin, apolipoprotein E, fibronectin and actin was examined. Protein synthesis was studied both at the protein level and at the RNA level by means of biosynthetic labeling, immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by Northern blot analysis of total RNA. After exposure to dexamethasone for 20 hr, alpha 2-macroglobulin protein synthesis was increased threefold, whereas apolipoprotein E expression was decreased 80%. Biosynthesis of fibronectin remained unaffected by hormone treatment. The dexamethasone effect became detectable 5 hr after beginning the exposure. Deinduction kinetic experiments showed that the glucocorticoid effect was detectable more than 12 hr after the replacement of the dexamethasone-containing culture medium by medium without the hormone. Corresponding to the data obtained at the protein level, dexamethasone increased the steady-state levels of alpha 2-macroglobulin-specific messenger RNA and reduced apolipoprotein E-specific transcripts, whereas fibronectin and actin messenger mRNA remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Transforming growth factor-β-induced collagen synthesis by human liver myofibroblasts is inhibited by α2-macroglobulin

“…a2M could not be demonstrated in cells or supernatants of cell cultures that were not supplemented with czzM-Me, indicating that human liver myofibroblasts did not produce arzM in culture. This is in contrast to observations on cultures of human fibroblasts derived from skin and lung (57,58), and rat FSC (42,59,60). The difference in azM production between human and rat FSC may be explained by species differences, as has also been observed for other features of FSC (61,62).…”

“…Alternatively, differences in the state of activation of the human and rat FSC used may explain the variation in a2M production. All studies on rat FSC (42,59,60) were performed in primary cultures between 5 and 11 days after isolation of cells, whereas we used human liver myofibroblasts between passages 2 and 9.…”

Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes

“…Our results showing the lack of hepatic apoE regulation by dexamethasone in both murine primary hepatocytes and HepG2 cells do not diverge significantly from the results of Staels and co-workers, who found that apoE gene expression in rat liver was only slightly decreased after dexamethasone administration [38]. However, another study reported that in cultured fat-storing Ito cells from rat liver, apoE expression was reduced 80% by dexamethasone [43]. …”

Immunocytochemical Localization of Bovine Serum Albumin (BSA) in the Liver and Testis of Rats injected with Testosterone-BSA, Hydrocortisone-BSA or Corticosterone-BSA.

“…A synthetic glucocorticoid, dexamethasone, affects the gene expression of hepatic stellate cells isolated from rat liver (Ramadori et al, 1991). Hepatic stellate cell nuclei exhibit immunoreactivity for glucocorticoid receptors (Raddatz et al, 1996).…”