An iron-deficient diet stimulates the onset of the hepatitis due to hepatic copper deposition in the Long-Evans Cinnamon (LEC) rat

Abstract

To study effects of dietary Cu and Fe levels on the onset of hepatitis in Long-Evans Cinnamon (LEC) rats, female rats (40 days old) were fed a semipurified diet containing 0.1 or 10 mg Cu/kg and 1.5 or 150 mg Fe/kg in a 2 x 2 factorial arrangement for 35 days. At 75 days after birth, LEC rats (+Cu-Fe) fed a Cu-sufficient but Fe-deficient diet (Cu, 10 mg/kg; Fe, 1.5 mg/kg) showed jaundice, with lethargy, anorexia, and malaise. The biochemical variables relating to liver function were significantly increased compared to three other groups, a Cu- and Fe-deficient (-Cu-Fe) group, a Cu-deficient but Fe-sufficient (-Cu+Fe) group, and a Cu and Fe sufficient (+Cu+Fe) group. Furthermore, the +Cu-Fe rat liver showed massive necrosis with huge nuclei. The other three groups presented no biochemical and histological findings of hepatitis. Hepatic Cu and metallothionein concentrations were 289 +/- 87 (mean +/- SD) microg/g liver and 8.7 +/- 1.8 mg/g liver, respectively, in the +Cu-Fe rats. However, in the +Cu+Fe group the values were 196 +/- 28 microg Cu/g liver and 10.8 +/- 1.0 mg/g liver. Hepatic Fe deposition was not influenced significantly by the dietary Cu level. The +Cu-Fe group with jaundice showed the highest free Cu concentration in the liver among the four groups, but the hepatic free Fe concentration was similar to those in the -Cu+Fe and +Cu+Fe groups. Our results indicate that an Fe-deficient diet enhances the deposition of hepatic Cu due to increased absorption of Cu from the gastrointestinal tract. This deposition stimulated the onset of hepatitis.

Mild zinc deficiency and dietary phytic acid accelerates the development of fulminant hepatitis in LEC rats

“…Deprivation of Fe prevents spontaneous fulminant hepatitis and liver cancer in LEC rats 36 . In contrast, several reports have shown that a Fe deficient diet stimulated the onset of the hepatitis in LEC rats 37,38 . From the results of our study, the reduction of Fe in the liver positively affected the development of hepatitis in LEC rats.…”

Exploration of the copper-related compensatory response in the Belgrade rat model of genetic iron deficiency

“…In this scenario, one would predict that there would also be increases in the copper import machinery, with Dmt1 being a potential player in this process. The possibility that iron deficiency enhances intestinal copper absorption, which contributes to hepatic copper loading, has in fact been previously proposed (51), and increased copper levels in duodenal tissue were reported in iron-deficient rats (43); however, the role of Dmt1 is not clear. The present studies were designed to examine the role of Dmt1 in copper homeostasis during iron deficiency by taking advantage of a naturally occurring Dmt1 mutation in the Belgrade rat.…”

Possible role of zinc and iron in the development of hepatic abnormality in Long‐Evans Cinnamon rats

“…Sugawara et al . demonstrated that a Fe‐deficient diet enhanced the deposition of hepatic Cu due to the increased absorption of Cu from the gastrointestinal tract 12 . This deposition stimulated the onset of hepatitis.…”

“…Sugawara et al . postulated that an increased dietary Fe level inhibited Cu absorption, but a deficit of Fe in the diet enhanced Cu absorption from the gastrointestinal tract; the accumulated Cu initiated the hepatitis in the LEC rats 12 . However, they did not clearly indicate if the Fe level in the liver was intrinsically involved in the development of hepatitis.…”

“…and Sugawara et al . indicated the opposite observation in the relationship between Fe contents and hepatic abnormality; that is, the reduction of Fe contents initiated or accelerated hepatitis due to hepatic Cu deposition in the LEC rat 4,12 . Saito et al .…”