Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Abstract

Hepatic iron deposition unrelated to hereditary hemochromatosis occurs commonly in cirrhosis but the pathogenesis of this condition is unknown. The aim of this study was to compare the expression of genes involved in the regulation of iron metabolism in cirrhotic (n ¼ 22) and control human livers (n ¼ 5). Transcripts were quantitated by real-time RT-PCR and protein levels were assessed by western blot. Hepatic iron concentrations (HICs) were measured by a spectrophotometric method. Levels of hepcidin mRNA did not differ between controls and cirrhotic livers; there was a highly significant correlation between hepcidin transcript levels and HIC in the latter group. Ferroportin, divalent metal transporter-1 (DMT1), and ferritin heavy chain mRNA levels were significantly higher in cirrhotic human livers than in controls (P ¼ 0.007, 0.039, and 0.025, respectively). By western blot, ferroportin and DMT1 levels were generally diminished in the cirrhotic livers compared to controls; neither correlated with HIC. In contrast, the abundance of ferritin increased with increasing HIC in the cirrhotic livers, whereas transferrin receptor decreased, indicating physiologically appropriate regulation. In conclusion, hepcidin expression appears to be appropriately responsive to iron status in cirrhosis. However, there are complex alterations in DMT1 and ferroportin expression in cirrhotic liver, including decreases in ferroportin and DMT1 at the protein level that may play a role in aberrant regulation of iron metabolism in cirrhosis.

Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans

“…26 HCV-positive samples obtained during routine patient work-ups were stained with hematoxylin and eosin (H & E) or Masson's trichrome and scored blindly for fibrosis and necroinflammatory activity using a METAVIR scoring system 27 as described previously. 28 Patients studied were designated HCV-positive if their serum tested positive in an enzyme-linked immunosorbent assay (EIA.3) for HCV antibodies.…”

Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute‐on‐chronic liver failure

“…9 Accumulation of iron in macrophages has been reported as an indicator of secondary iron overload status in CLD. 10 Down-regulation of circulating transferrin (Tf ) and its receptor has also been reported in liver cirrhosis (LC) patients, 11 which correlates with a raised Tf saturation index (%SAT). 12 We have recently reported on the significance of elevated serum ferritin levels in patients with decompensated CLD as a predictor of early mortality.…”

The effect of ursodeoxycholic acid on Messenger RNA hepcidin expression associated with liver fibrosis in perposed cholestasis jaundice

“…Obstructive jaundice (OJ) increases the risk of liver injury and sepsis, leading to increased mortality [6,7,[11][12][13][14][15][16][17].…”

“…expression results more bacterial infections and mortality are higher, which confirms the importance of gp130 in innate immunity and IL-6 signaling.37 intrahepatic Stat3 activation predictable outcome, 38 and STAT3 knockout mice showed significantly higher death of widths after cecal ligation and puncture sepsis. Kano et al have shown that STAT3 signaling in the endothelium have anti-inflammatory as an important mediator of the endotoxin-induced inflammation [11,12].…”

“…Hepcidin mRNA expression can be done through qRT-PCR, or ELISA assay of plasma hepcidin. Increased Plasma hepcidin is proven associated with progression of liver fibrosis and correlated with prognosis [10][11][12][13].…”