Role of iron in hepatic fibrosis: one piece in the puzzle

Abstract

Iron is an essential element involved in various biological pathways. When present in excess within the cell, iron can be toxic due to its ability to catalyse the formation of damaging radicals, which promote cellular injury and cell death. Within the liver, iron related oxidative stress can lead to fibrosis and ultimately to cirrhosis. Here we review the role of excessive iron in the pathologies associated with various chronic diseases of the liver. We also describe the molecular mechanism by which iron contributes to the development of hepatic fibrosis.

Figure 1

The involvement of iron in oxidative stress and its cytotoxic conse-quences. Iron catalyses the production of the reactive molecules OH^• (via the Fenton reaction) and NO₂⁺, which promote lipid peroxidation and protein damage leading to cellular injury. NOS, nitric oxide synthase; ^•NO, nitric oxide; ONOO^-, peroxynitrite; O2^•-, superoxide radical; OH^•, hydroxyl radical; H₂O₂, hydrogen peroxide; NO₂⁺, nitronium anion; Fe, iron; NAFLD, non-alcoholic fatty liver disease.

Figure 2

Mechanisms of iron-induced liver injury and fibrosis. Iron catalyses the formation of several reactive oxygen species in hepatocytes. Under normal circumstances, hepatocytes are able to effectively cope with oxidant stress. When the liver is subjected to a secondary insult that enhances hepatic oxidant stress, hepatic fibrosis begins to develop. Increased oxidative stress and other pathological modes of action of HCV, ethanol and steatosis, lead to mitochondrial dysfunction and hepatocyte apoptosis. Kupffer cell activation is achieved by phagocytosis of apoptosing hepatocytes in conjunction with the direct effects of iron, HCV infection, ethanol and steatosis on Kupffer cells. The concomitant hepatocyte damage/apoptosis and Kupffer cell activation is able to drive and maintain hepatic stellate cell activation leading to fibrosis and ultimately cirrhosis if left unchecked. Fe, iron; TF, transferrin; ROS, reactive oxygen species; FA, fatty acids; IR, insulin receptor; GSH, glutathione; TNFα, tumour necrosis factor α; NO, nitric oxide; IL-6, interleukin 6; TGFβ1, transforming growth factor β1; CTGF, connective tissue growth factor; αSMA, α smooth muscle actin; MDA, malondialdehyde; 4HNE, 4-hydroxynonenal; MIP-1, macrophage inflammatory protein-1; TGFα, transforming growth factor α; NF-κB, nuclear factor κB; AP-1, activating protein-1.