*Regulation of Iron Metabolism in NAFLD/NASH DOI: http://dx.doi.org/10.5772/intechopen.107221*

role in controlling the dietary absorption of iron, its storage and its release into the bloodstream. Hepcidin concentrations are strictly controlled, and their pathologic dysregulation leads to numerous human iron-related disorders such as NAFLD/ NASH. Our understanding of hepcidin regulation has rapidly increased; however, numerous questions related to hepcidin pathobiology still need to be clarified and addressed [18].

Iron is stringently and elegantly regulated by a mechanism similar to that for glucose control [19]. Like glucose and insulin, the serum iron levels are regulated by a hepatic peptide hormone, hepcidin. Elevated iron levels arouse hepcidin synthesis, which decreases the levels of the iron-exporter ferroportin in macrophages and intestinal cells and reduces serum iron levels, similar to how insulin controls excessive glucose levels [19, 20].

The spectrum of NAFLD ranges from simple steatosis to NASH [21]. Iron is regarded as a putative element that interacts with oxygen radicals, and NASH is associated with high rates of hyperferritinemia together with increased hepatic iron stores [22]. The role of hepatic iron in the progression and pathogenesis of NASH remains unclear and controversial.

It stands to reason that iron is one of the most copious metals on the earth with the potential of high toxicity against living cells. Highly active cells need iron for maintaining their metabolic activity because iron allows optimal and preferable electron transfer, assisting biochemical reactions between different atoms and molecules. The toxicity of iron originated from induction of reactive oxygen species (ROS), which at high levels leads to cellular damage [23, 24]. Progress in understanding the involvement of hepcidin in normal physiology and disease conditions [25], coupled with advances in quantification, make it an increasingly attractive candidate biomarker for assessing iron status and guiding iron intervention strategies [26]. Evidence suggests that a modest degree of iron overload is associated with more advanced liver injury in NAFLD, although the mechanisms by which this might occur remain unclear and vague [27, 28].

Recently, however, it has become increasingly evident that iron in the adipose tissue plays an important role in the pathogenesis of insulin resistance and, therefore, possibly NAFLD [29, 30].

Excessive iron is also a potent cause of cellular injury from oxidative stress due to the generation of reactive oxygen species by the Fenton reaction [31]. Under usual conditions, intracellular protection from iron-induced oxidative stress is facilitated by the sequestration of iron within ferritin [32]. Dysfunctional adipose tissue produces adipokines that promote the development of insulin resistance [29]. The liver, skeletal muscle and adipose tissue are the key sites of insulin action and resistance [33]. In the adipose tissue itself, insulin resistance potentiates lipolysis of triglycerides by the hormonesensitive lipase [34]. This generates the most free fatty acid (FFA) flux in the liver in NAFLD [35]. Insulin resistance in skeletal muscle as a result leads to reduced uptake of glucose, on the other hand in the liver, insulin resistance enhances gluconeogenesis [36]. Iron and NAFLD-resultant compensatory hyperinsulinemia and relative hyperglycaemia promote hepatic de novo lipogenesis and cholesterol synthesis and reduced catabolism of FFA by oxidation [37]. Oxidative stress is considered an important contributor to the pathogenesis of NASH [38]. Excess hepatic iron can promote oxidative stress via Fenton's reaction and is proposed to be a cofactor in the development of NASH.

The regulatory mechanisms of hepcidin have been investigated in animal models, and only a few studies have investigated the role of hepcidin in human NAFLD patients [39]. Hepcidin is an important regulator of liver inflammation [19], and along with its key role in iron homeostasis, it could play a vital part in NASH

pathogenesis. It was hypothesised that hepcidin and/or its upstream regulatory factors play a key role in the progression of NAFL to NASH [40]. The elevated hepcidin in NASH seems to be either a reflection of hepatocellular inflammation or simply indicating the induced hepcidin in the early stage of NASH. Hepcidin expression actually appears to be directly enhanced by insulin and down-regulated under insulin resistance, suggesting a possible mechanism for iron loading as an early event in the pathogenesis of NAFLD and T2DM. These findings have raised numerous questions and have stimulated exciting clinical research. With that in mind, it is difficult to predict what additional surprises will emerge from the ongoing study of this fascinating viewpoint.

The elevated ferritin and low expression of hepatic inflammatory cytokines (IL-6; 8-fold, NFNB; 5-fold and IL-1E; 4-fold) in patients with NAFLD with hepatic iron deposition could probably be suggestive of the notion that in this cohort, increased hepcidin expression is more likely attributable to hepatic iron deposition rather than inflammation.

Hepatic HAMP gene expression is induced in patients with NASH compared to that in patients with NAFLD, and presumably, in response to excess hepatic iron in NAFLD patients with iron overload. Two possible mechanisms for hepcidin expression in patients with NASH are likely IL-6-mediated stimulation of JAK2/STAT3 pathway, which results in upregulation of HIF1D. Furthermore, increased hepatic *STAT3* gene expression in NASH patients relative to that in NAFLD patients lends support to this putative hypothesis.

The presence of iron deposition in livers of patients with NAFLD can be classified as hepatocellular, reticuloendothelial or both. A study of 849 adult biopsy specimens performed in the United States showed that reticuloendothelial patterns of iron deposition were associated with advanced fibrosis compared with hepatocellular iron patterns. Biopsy specimens with reticuloendothelial iron were also more likely to have definite steatohepatitis [41]. However, an Italian study on 587 patients with NAFLD found that hepatocellular rather than reticuloendothelial iron was associated with an increased likelihood of liver fibrosis [42].

The reason for the discordant results might be explained by the differences in the patient populations; the subjects in the US study were more ethnically diverse and had higher body mass indices and more advanced fibrosis than those in the Italian study. Interactions between iron metabolism and NAFLD are complex and complicated under active investigation by various researchers. In conclusion, they observed that HAMP expression is elevated in NASH patients and in NAFLD patients with hepatic iron deposits. Their data allowed them to study the interdependence of various regulatory signals such as hepatic iron stores, inflammation and hypoxia or oxidative/ER stress on the expression of hepcidin and inflammatory cytokines. Increased hepcidin expression, which attempts to sequester excess iron, thereby reducing oxidative stress, maybe a protective response.

Bekri et al. showed that hepcidin levels are increased in the adipose tissue of severely obese patients compared with those in the liver, suggesting that severe obesity itself causes hypoferremia due to the overproduction of hepcidin in the adipocytes [43].

Asian Indians are neither associated with iron overload nor with *HFE* gene mutations [44].

The authors suggested that hyperferritinemia in NASH is a non-specific effect of hepatic necroinflammation, reflecting its function as an acute phase protein as a result. Serum ferritin is known to increase because of released from damaged hepatocytes. The authors also previously concluded that serum ferritin levels reflect
