Excess iron induces hepatic oxidative stress and transforming growth factor ?1 in genetic hemochromatosis

Abstract

the absence of inflammation. TGF-b1 mediates many cellular Genetic hemochromatosis (GH) is associated with excess functions, including growth stimulation and inhibition, iron deposition in hepatocytes, which results in progressive apoptosis, increased extracellular matrix protein synthesis, hepatic injury. The pathogenesis of hepatic injury in GH is and decreased extracellular matrix degradation. [8][9][10][11][12] The colopoorly understood. In this study, we found enhanced oxidacalization of increased hepatic collagen a1(I) mRNA with tive stress in patients with GH, as evidenced by hepatic malon-TGF-b1 immunostaining suggests that TGF-b1 may also be dialdehyde (MDA)-protein adducts and by increased oxidaimportant in hepatic fibrogenesis associated with iron overtively modified serum proteins. MDA-lysine epitopes and load. The molecular mechanisms of TGF-b1 induction in oxidatively modified serum proteins, as well as immunogloburesponse to excess iron and enhanced lipid peroxidation in lin G autoantibodies against MDA-lysine epitopes, were inthe animal model of hemochromatosis are not known. creased in untreated GH patients and to a lesser extent in Iron directly or through the induction of cytokines, such GH heterozygotes compared with normal individuals. These as TGF-b1, could also play an important role in the developmarkers of ongoing oxidative stress decreased with phlebotment of liver injury 13-15 because excess iron removal in preomy treatment in GH patients. In addition, TGF-b1 colocalcirrhotic patients with GH prevents the development of fibroized with hepatic iron and MDA protein adducts in hepatosis and hepatocellular carcinoma formation. 16 However, it is cytes and sinusoidal cells of hepatic acinar zone 1 and not known whether excess hepatic iron in patients with GH normalized after iron removal. Our data suggest that iron is also associated with increased lipid peroxidation and TGFoverload increases both lipid peroxidation and TGF-b1 exb1 expression. In this study we analyzed whether hepatic pression, which together could promote hepatic injury and iron overload induces lipid peroxidation and TGF-b1 expresfibrogenesis. (HEPATOLOGY 1997;26:605-610.) sion in patients with GH. Genetic hemochromatosis (GH) is associated with excess PATIENTS AND METHODSiron deposition in hepatocytes, which results in hepatic injury. 1,2 The mechanisms responsible for the development of hydrazine to form a hydrazone complex, which was measured specof California, San Diego, CA; and 2 The Joint Liver Program, University of Queensland trophotometrically as described. 17 The hydrazone derivative has a

Oxidative stress and steatosis are cofactors of liver injury in primary biliary cirrhosis

“…The metabolic factors associated with obesity and steatohepatitis, such as insulin resistance and altered adipokine levels, may also contribute to enhanced fibrosis, as has been shown in other liver diseases [49][50][51][52][53][54][55], but this should be prospectively and specifically addressed in future studies of PBC. It is well known that iron-induced oxidative stress leads to hepatic lipid peroxidation and HSC activation [39,[56][57][58][59][60], but according to our results in asymptomatic PBC, iron alone does not appear to have a strong enough effect to serve as an independent predictor for the severity of liver damage. In animal models, susceptibility to iron-induced fibrosis is markedly increased by the prior activation of Kupffer cells by other toxins or ligands [39,61] and by steatosis itself, as well as by alcohol consumption, which may be accompanied by abnormalities in Kupffer cell function and cytokine production [62,63], in addition to augmenting the production of ROS and providing a substrate for lipid peroxidation [33,64,65].…”

Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis

“…Moreover, liver iron overload, which is frequent in patients with hepatitis C viral infection, [15][16][17] may exert a carcinogenetic effect thereby facilitating the development of HCC [18][19][20]. Oxidative stress, which involves the production of iron catalysed oxyradicals, is generally considered to be the main mechanism underlying the progression of fibrosis to cirrhosis and HCC in genetic hemochromatosis [21,22]. However, iron overload may have a detrimental effect also in some chronic liver diseases irrespective of hemochromatosis [23].…”

Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes

“…Expression of BMP6 and TGF-␤1 is induced in iron-loaded hepatocytes (26), and thus, TGF-␤1 superfamily members may contribute to the hepcidin-controlled reduction of dietary iron uptake. In contrast to BMP6-controlled hepcidin expression, which requires the hepatocytic cell surface receptors ALK2 and ALK3, we show that TGF-␤1-dependent hepcidin induction is mediated by ALK5.…”

“…TGF-␤ expression is increased in response to liver damage and enhances hepatocyte destruction, as well as hepatic stellate cell activation, resulting in myofibroblast generation and extracellular matrix deposition (25). In HH patients, immunostaining of TGF-␤1 is markedly increased in liver biopsies and normalized following phlebotomy, suggesting that it may contribute to progressive hepatic injury in HH patients (26). Whether or not TGF-␤1 is induced by iron accumulation or liver damage in HH patients remains unclear.…”