Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets

Long-Xia Li; Fang-Fang Guo; Hong Liu; Tao Zeng

doi:10.1007/s00018-022-04239-9

. 2022 Mar 24;79(4):201. doi: 10.1007/s00018-022-04239-9

Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets

Long-Xia Li ¹, Fang-Fang Guo ², Hong Liu ¹, Tao Zeng ^1,^✉

PMCID: PMC11071846 PMID: 35325321

Abstract

Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.

Keywords: Alcoholic liver disease, Iron overload, Hepcidin, Ferroptosis

Introduction

Alcoholic liver disease (ALD) represents a spectrum of progressively aggravated liver damage ranging from steatosis to hepatitis, fibrosis, and cirrhosis. Although the deleterious effects of ethanol have been widely recognized, the global amount of alcohol consumption and incidence of ALD is still rising [1]. In terms of geographical distribution, the European region has the highest levels of alcohol consumption and incidence of ALD [2]. In the US, retrospective analyses of three databases revealed that the proportion of ALD with stage ≥ 3 fibrosis was significantly increased (from 2.2 to 6.6%) from 2001–2002 to 2015–2016, although the overall weighted ALD prevalence was stable (from 8.8 to 8.1%) [3]. In Asia, alcohol consumption was reported to be increasing in many countries including Korea and China [4, 5]. Undoubtedly, ALD remains to be a worldwide public health challenge. Unfortunately, there are no effective pharmaceutical drugs for ALD treatments, and abstinence is still the most effective strategy for the prevention of disease progression [6]. Therefore, it is urgently needed to screen effective medicines and identify new therapeutic molecular targets.

The development of ALD is extremely complex, and both genetic and nongenetic factors are reported to be involved. Nongenetic factors include reactive oxygen species (ROS) and oxidative stress, the toxicity of acetaldehyde, activation of Kupffer cells (KCs), cytokines, the gut–liver axis, etc. [7]. Iron is an essential trace element that takes part in many biological activities such as metabolism, oxygen transport, innate immunity, and DNA synthesis [8, 9]. However, excessive iron accumulation could induce liver damage by inducing oxidative stress and iron-dependent cell death, namely ferroptosis [10, 11]. Ferroptosis, characterized by iron-dependent damage and subsequent plasma membrane ruptures, is a new form of regulated cell death [12–14]. The damage-associated molecular patterns (DAMPs) released by the ferroptotic hepatocytes will activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in KCs followed by increased release of proinflammatory cytokines and chemokines [15, 16]. It should be noted that even mild to moderate drinking could increase iron accumulation in the liver [17, 18]. Iron overload in the liver is a hallmark of ALD, which may have both diagnostic and prognostic value for ALD [19, 20]. Herein, we review the current knowledge on iron homeostasis, molecular mechanisms underlying ethanol-induced iron overload, detrimental effects of iron overload, diagnostic and prognostic roles of molecules in iron homeostasis, and potential therapeutic targets. In addition, we compared the similarities and differences of iron overload in ALD and nonalcoholic fatty liver disease (NAFLD).

Iron homeostasis: metabolism and regulators

Iron absorption, recycling, and storage

Adults contain approximately 3–5 g iron, and more than 80% is presented in the hemoglobin of erythrocytes, while the other 20% is stored transiently within macrophages and hepatocytes [21, 22]. There are two sources of iron in the body, i.e., endogenous iron and exogenous iron, which refer to the recycling iron from the senescent erythrocytes and the dietary iron, respectively. Macrophages play a major role in iron recycling by erythrophagocytosis, the process of clearance of senescent/damaged erythrocytes. The heme is decomposed by heme oxygenase 1 (HO1) and the iron is released and recycled back into circulation through the only known iron exporter ferroportin (FPN) [23, 24]. Dietary heme iron (Fe²⁺) and non-heme iron (Fe³⁺) are absorbed in the apical membrane of duodenal enterocytes through different mechanisms [25]. The trivalent iron (Fe³⁺) is not bioavailable and needed to be reduced into ferrous form (Fe²⁺) by duodenal cytochrome b (DcytB), which is then absorbed into enterocytes by the divalent metal transporter-1 (DMT1) in the apical surface of enterocytes [26]. The ferrous Fe²⁺ is exported into circulation by the FPN located in the basolateral membrane of intestinal cells [27]. The pathway for heme iron absorption is less defined, and current hypotheses suggest that heme iron is absorbed through receptor-mediated endocytosis or heme carrier protein 1 (HCP1)-mediated transport into the cytoplasm [28, 29]. Once in the epithelial cells, heme iron is catabolized possibly by HO1 and the released iron enters the same pathway as the non-heme iron [25, 30].

Intracellular irons are tightly bound to either proteins or small molecular ligands and sequestered in specific pools to avoid toxic effects. Specifically, most of the iron in circulation exists in Fe³⁺ form, tightly bound to transferrin, and is used for the synthesis of hemoglobin by erythrocytes [31]. The Fe²⁺ absorbed and from recycling is oxidized to Fe³⁺ form by two copper-containing oxidases, ceruloplasmin (CP) or the homolog hephaestin [32, 33], which is essential for efficient binding to transferrin. Transferrin delivers iron into cells via binding with the transferrin receptor (TfR) [34]. Excess iron is usually stored in the liver and sequestered in the major cellular iron-storing protein, ferritin, a hollow globular protein composed of many subunits which can store up to 4500 ferrous ions [35]. When the iron demand increases, the liver can mobilize the stored iron to increase the iron content in circulation [21] (Fig. 1).

Fig. 1 — Iron homeostasis in the body. There are two sources of iron in the human body, i.e., endogenous iron and exogenous iron, which refer to recycling iron from senescent erythrocytes and dietary iron, respectively. Dietary iron exists in the form of the heme (Fe²⁺) and non-heme (Fe³⁺), which are absorbed in the top of duodenal intestinal epithelial cells through different mechanisms. Divalent metal transporter 1 (DMT1) at the apical membrane of enterocytes takes up Fe²⁺ from the lumen, and duodenal cytochrome b (DcytB) is responsible for the reduction of dietary Fe³⁺ to Fe²⁺. Ferroportin (FPN) at the basolateral membranes exports Fe²⁺ into the blood. Macrophages can recycle heme-derived iron from senescent erythrocytes and release iron through FPN to blood. The Fe²⁺ is oxidized to Fe³⁺ form by ceruloplasmin (CP), which is essential for efficient binding to transferrin. Up to 80% of iron is presented in the hemoglobin of erythrocytes, while excess iron is usually stored in ferritin in the liver

Regulation of iron homeostasis

Iron homeostasis in the human body is tightly controlled by the critical hormone hepcidin synthesized by the hepatocytes, which could regulate iron absorption and exportation by working with FPN. Duodenal cells, macrophages in the spleen and liver, and hepatocytes are iron exporting cells, which can release iron into circulation through FPN [36]. Hepcidin could form complex with FPN leading to the internalization and degradation of FPN protein and stoppage of cellular iron exportation from duodenal cells and macrophages [37, 38]. The liver can sense both intracellular and extracellular iron concentrations and regulate the production of hepcidin through the bone morphogenetic protein (BMP)/SMAD pathway [39–41]. Iron homeostasis is intimately tied to the inflammatory response [42]. Iron overload could aggregate the inflammatory responses, while proinflammatory cytokines such as interleukin 6 (IL6), IL1β, and IL22 may suppress the iron absorption by increasing the production of hepcidin [21, 43–45]. The induction of hepcidin expression in response to IL6 was demonstrated to be mediated by the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway [46–48], while a potential interaction between STAT3 and BMP/SMAD signaling may be also involved in the induction of hepcidin under inflammatory condition [40, 49]. Hepcidin expression will be repressed in cases of iron deficiency, hypoxia, and hemorrhage [18, 37, 39]. The suppression of hepcidin expression in hypoxia is mediated by the hypoxia-inducible factors (HIFs), which may inhibit the transcription of hepcidin by directly binding to its gene promoter or by increasing the erythropoiesis activity [50, 51]. Erythropoietin (EPO) secreted by the kidney is a main driving force for the proliferation and differentiation of erythroid progenitor cells [52]. EPO could repress hepcidin expression in hepatocytes probably by regulating the activity of transcription factor CCAAT/enhancer-binding protein α (C/EBPα) [53]. In addition, the suppression of EPO on hepcidin expression may be related to the erythroferrone (ERFE) produced by erythroblasts in response to EPO, which could target hepatic BMP/SMAD signaling via preferentially impairing an evolutionarily closely related BMP subgroup of BMP5, BMP6, and BMP7 [54–56]. Furthermore, the expression of hepcidin may also be affected by growth factors and sex hormones. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) have been demonstrated to suppress the expression of hepcidin by interfering with the BMP/SMAD pathway [57]. Testosterone can inhibit hepcidin expression, but whether estrogen could affect hepcidin expression is still unclear [58–60].

In addition to the hepcidin/FPN system, the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) system also plays an important role in maintaining iron homeostasis [61, 62]. IRPs control the mRNA translation or stability by binding with IREs motif (CAGUGN) in the untranslated regions of target mRNAs encoding iron acquisition, storage, utilization, and export [63, 64]. Under iron overload conditions, IRPs interact with the F-box and leucine-rich repeat protein 5 (FBXL5) adaptor protein that recruits an SCF (SKP1-CUL1-F-box) E3 ligase complex, promoting IRPs ubiquitination and subsequent degradation by the proteasome [65, 66]. The dissociation of IRP-IRE interaction will promote the translation of ferritin and FPN mRNA and destabilize TfR and DMT1 mRNA, resulting in the decline of iron absorption and increase of iron storage and export [67, 68]. In contrast, FBXL5-dependent IRPs degradation will decrease in iron-deficient cells, and thus, the interaction between IRPs and the IRE motif in the 5′-UTR of ferritin and FPN will inhibit the translation, while the binding of IRPs to an IRE at the 3′-UTR of TfR1 can protect mRNA against endonuclease cleavage [67]. As a consequence, TfR1-mediated iron uptake increases, whereas iron storage in ferritin and export via FPN will decrease [69].

Ethanol-induced iron overload and the underlying mechanisms

Iron overload in ALD

It has been well demonstrated that ethanol exposure could induce iron overload in human beings and laboratory animals evidenced by the increase of serum/hepatic iron levels, serum ferritin level, and transferrin saturation (TS) [18, 70, 71]. Serum iron and ferritin levels increased linearly with daily alcohol consumption, while serum ferritin levels decreased rapidly during abstinence [71, 72]. Besides, drinking frequency was found to be correlated with the levels of serum iron, iron-binding capacity, TS, and hemoglobin concentration in boys [73]. More importantly, a great number of laboratory and clinical studies have highlighted that iron overload may promote the progression of ALD. For instance, the liver iron level was found to be negatively correlated with the survival of ALD patients, suggesting that iron overload is an independent risk factor for fibrosis in ALD [74]. One recent study suggested that serum transferrin could serve as an independent predictor of mortality in severe alcoholic hepatitis [75]. Furthermore, animal studies demonstrated that dietary carbonyl iron could promote the liver damage induced by ethanol feeding in rats [76, 77].

The molecular mechanism of ethanol-induced iron overload in the liver

How does ethanol induce iron overload in the liver? Both in vivo and in vitro studies have revealed that ethanol exposure could downregulate mRNA and protein expression of hepcidin [78–81]. The downregulation of hepcidin expression could upregulate the expression of DMT1 and FPN in the duodenum leading to increased iron absorption, which could be abrogated by injection of hepcidin peptide [81, 82]. Ethanol exposure may repress hepcidin expression via several mechanisms. First, ethanol metabolism-mediated oxidative stress could suppress hepcidin transcription via inhibiting C/EBPα. An elegant study by Harrison-Findik et al. found that the hepcidin mRNA and protein levels were significantly decreased in ethanol-exposed mice liver and in HepG2 cells transfected with ethanol-metabolizing enzymes, which could be abolished by 4-methylpyrazole, a specific inhibitor of alcohol metabolizing enzymes [78]. Interestingly, antioxidants including vitamin E and N-acetylcysteine (NAC) attenuated the suppression of ethanol on hepcidin expression, the promoter activity of hepcidin, and the DNA binding activity of C/EBPα, suggesting that oxidative stress contributed to the decline of hepcidin expression after ethanol exposure [78]. Second, Ethanol exposure could induce HIFs expression and promote the production of EPO in HepG2 cells, primary liver and kidney cells, and in mice [83, 84]. These results suggest that the elevation of EPO may also be involved in the decline of hepcidin expression, as EPO has been demonstrated to inhibit hepcidin expression probably by regulating the C/EBPα activity and BMP/SMAD signaling [53–56].

In addition to suppressing hepcidin expression, ethanol may induce iron accumulation in the liver by acting on TfR. TfR expression was found to be upregulated in the hepatocytes of ALD patients [85]. The following in vitro study using rat primary hepatocytes showed that ethanol and iron exposure (20 μM iron and 25 mM ethanol) induced TfR expression and transferrin-bound iron uptake partially through the activation of IRPs [86]. In contrast, ethanol alone (25 mM) did not change the mRNA expression of TfR1 and IRP2, and the RNA-binding activity of IRP1 in hepatocytes transfected with ethanol-metabolizing enzymes [78]. These results suggest that ethanol may work with the accumulated iron to induce TfR expression. Interestingly, one recent study found that intestinal sirtuin 1 (SIRT1) deficiency could normalize ethanol-induced increase of hepatic iron to nearly control levels, suggesting that SIRT1 plays a crucial role in the iron overload in ALD [87]. Lipocalin-2 (LCN2) secreted by neutrophils is an siderophore-sequestering protein, and the Holo-LCN2 (Lcn2–siderophore–iron, 1:3:1) could regulate iron metabolism [88]. As SIRT1 deficiency suppressed the ethanol-induced increase of Holo-LCN2, intestinal SIRT1 deficiency might attenuate ethanol-induced iron overload by acting on LCN2 [87] (Fig. 2).

Fig. 2 — The molecular mechanisms of ethanol-induced iron overload in the liver. Ethanol may induce iron overload in the liver by multiple mechanisms. (1) Ethanol may upregulate transferrin receptor (TfR) expression by activating iron-regulatory proteins (IRPs) to increase iron absorption; (2) oxidative stress induced by ethanol may reduce the expression of hepcidin by inhibiting the activity of transcription factor CCAAT/enhancer-binding protein α (C/EBPα); (3) ethanol metabolism can induce hypoxia and promote the production of hypoxia-inducible factors (HIFs) and erythropoietin (EPO), leading to the inhibition of transcription of hepcidin by acting on C/EBPα; (4) EPO may suppress the hepcidin expression by erythroferrone (ERFE)-mediated suppression on the bone morphogenetic protein (BMP)/SMAD signaling. (5) The inhibition of the BMP/SMAD pathway may impair the activation of hepcidin via STAT3 in response to inflammatory cytokines. Downregulation of hepcidin expression leads to increased expression of divalent metal transporter 1 (DMT1) and ferroportin (FPN) in the duodenum, leading to increased intestinal iron absorption

The roles of KCs in the development of ALD have been highlighted; however, neither inactivation of KCs nor neutralization of tumor necrosis factor α (TNFα) reversed ethanol-induced suppression of hepcidin expression, indicating that KCs are not involved in the decline of hepcidin expression in ALD [89]. Theoretically, the proinflammatory cytokines secreted by activated KCs after ethanol exposure could induce hepcidin expression via activating the JAK/STAT3 pathway [46]. Interestingly, STAT3-RE (response elements) was found to be located close to the proximal BMP-RE in the hepcidin promoter, and inactivation of BMP-RE severely suppressed IL6-mediated hepcidin expression [90, 91]. Therefore, the inactivation of BMP-RE by ethanol may abolish stimulation of proinflammatory cytokines on hepcidin expression, which may help to explain why hepcidin expression is downregulated but not upregulated in the ethanol-induced inflammatory liver. Whether KCs take roles in ethanol-induced iron accumulation via hepcidin-independent mechanisms remains to be elucidated.

Detrimental effects of iron overload in the liver

Iron overload may aggravate ALD by potentiating ethanol-induced oxidative stress, activating KCs and hepatic stellate cells (HSCs), and triggering ferroptosis in hepatocytes (Fig. 3).

Fig. 3 — The detrimental effects of iron overload in the development of ALD. Overloaded iron in the liver can promote the production of a large number of reactive oxygen species (ROS) through Fenton reactions, and thus induce oxidative damage of lipids, proteins, and DNA, and trigger ferroptosis of hepatocytes. In addition to the impairment on hepatocytes directly, iron-generated ROS and lipid peroxidation by-products such as 4-hydroxy-2-nonenal (4-HNE) may induce the activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs)

The most evident and generally accepted detrimental effect of iron accumulation is the production of ROS via Fenton reaction, in which hydrogen peroxide is converted into hydroxyl radicals in the presence of ferrous iron [92]. Iron-induced production of ROS will potentiate the oxidative stress induced by ethanol, resulting in oxidative damage to lipids, proteins, and DNA. Iron overload in the liver can induce an iron-dependent regulated cell death, defined as ferroptosis by Dixon et al. in 2012 [14]. Ferroptosis is induced by lethal lipid peroxidation, which could be abrogated by antioxidants and iron chelators [13]. It has been demonstrated that ferroptosis could be activated by suppression of cysteine uptake and inactivation of glutathione peroxidase 4 (GPX4) [93]. Ethanol feeding led to increased iron accumulation in the liver and upregulated biomarkers of ferroptosis including the increase of lipid peroxidation and NADPH, and the decline of reduced glutathione (GSH) level and GPX4 activity [87, 94]. Ferroptosis inhibitor, ferrostatin-1, significantly suppressed ethanol-induced lipid peroxidation and hepatocyte death both in vitro and in vivo, which was accompanied by the increased expression of the cystine/glutamate antiporter (system Xc⁻) and GPX4 [94]. Interestingly, intestinal sirtuin1 (SIRT1) deficiency attenuated ethanol-induced liver iron overload and mitigated ferroptosis [87]. Nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the cellular antioxidant response, plays a critical role in mitigating lipid peroxidation and ferroptosis [95]. NRF2 inducers prevented ethanol-induced lipid peroxidation, ferroptosis, and liver injury in mice [96]. Furthermore, frataxin, a mitochondrial protein involved in iron homeostasis and oxidative stress, has been demonstrated to be the upstream target of ethanol-induced ferroptosis [97].

In addition to the direct roles on hepatocytes, iron-generated ROS and lipid peroxidation by-products such as 4-hydroxy-2-nonenal (4-HNE) may induce the activation of KCs and HSCs [10, 21, 98, 99]. Treatment with iron led to increased mRNA expression of M1 markers in bone marrow-derived macrophages (BMDMs) and decreased mRNA expression of M2 markers in the presence of IL4 [100]. Ethanol-induced accumulation of iron in hepatic macrophages could prime nuclear factor-κB (NF-κB) activation, aggravating experimental alcoholic steatohepatitis [101–103]. Ethanol feeding has been demonstrated to increase the translocation of intestinal lipopolysaccharide (LPS) to the liver via the portal vein, where it activates the KCs into an M1 phenotype favoring the production of proinflammatory cytokines [104]. Importantly, it has been demonstrated that iron overload could potentiate the inflammatory response of macrophages to LPS possibly by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide [105]. Furthermore, Iron overload could promote HSCs activation, increased transforming growth factor β (TGF-β) expression, collagen deposition, and formation of fibrosis [106–109]. Iron chelation by deferoxamine inhibited the expression of platelet-derived growth factor receptor β (PDGFRβ) and smooth muscle α-actin (αSMA) and the proliferation of HSCs, while an iron-deficient diet suppressed liver fibrosis induced in a bile-duct ligation model [110]. Results of these studies suggest that iron overload may trigger activation of KCs and HSCs, promoting inflammation and fibrosis in ALD.

Comparison of iron overload between ALD and NAFLD

Given the critical role of the liver in iron metabolism, it is not surprising that disturbance of iron homeostasis is also involved in the development of NAFLD. Approximately, one-third of patients with NAFLD develop elevated serum ferritin (hyperferritinemia) and hepatic iron overload [111]. Serum TS was increased in iron-loaded NAFLD patients than in NAFLD patients without iron accumulation, while the hepatic TfR mRNA expression was significantly decreased [112–114]. Iron overload in NAFLD was characterized by a mixed pattern with iron deposits in both hepatocytes and KCs [115, 116]. Furthermore, serum ferritin level was reported to be an independent predictor of the severity of NAFLD [116–118].

However, the mechanisms of iron overload in NAFLD are different from ALD. In contrast to the downregulation of hepcidin and upregulation of FPN in ALD, NAFLD with iron overload is usually accompanied by higher hepcidin expression and lower FPN expression [112, 119]. The upregulation of hepcidin expression in NAFLD may be due to the inflammatory cytokines and the decline of iron sensing molecule hemojuvelin (HJV) [112, 120, 121]. Specifically, TNFα expression was higher in NAFLD patients without iron overload than in controls, with a further elevation in NAFLD patients with iron overload, while in vitro study showed that TNFα downregulated the mRNA expression of HJV and FPN in HepG2 cells [112]. The expression of duodenal DMT1 did not differ significantly among healthy controls, NAFLD patients with iron accumulation, and NAFLD patients without iron overload [112]. However, another study found that the oral iron absorption (100 mg of sodium ferrous citrate administered to each individual) from the gastrointestinal tract was indeed significantly increased in nonalcoholic steatohepatitis (NASH) patients compared with simple steatosis or control subjects, and the DMT1 mRNA expression in NASH patients were significantly elevated than the control group [122]. Furthermore, serum from NASH patients could induce DMT1 mRNA expression in Caco-2/TC7 cell monolayers possibly by the activation of IRP [122]. These results suggest that blockade of iron export and increased iron absorption may contribute the hepatic iron accumulation in NAFLD. Interestingly, the aggregation of erythrocytes in inflammatory hepatic sinusoids was notable in specimens from NASH patients, and the phagocytosis of fragile erythrocytes by KCs was observed in vitro [123]. These results indicate that the iron retention in macrophages may also be related to the enhanced erythrophagocytosis.

The detrimental effects of iron overload in NAFLD are similar to those in ALD, i.e., inducing oxidative stress, which may result in oxidative lipid, protein and DNA damage, endoplasmic reticulum stress, mitochondrial damage, induction of inflammatory and fibrogenic response, and ferroptosis [113, 124–127]. It has been demonstrated that serum iron and TfR could promote lipolysis in isolated adipocytes and reduce glucose uptake probably through a prooxidant mechanism and thus contribute to insulin resistance in NAFLD [128, 129]. TNFα could decrease hepatocyte sensitivity to insulin by reducing the expression of glucose transporter 4 (GLUT4) and by reducing the phosphorylation of insulin receptor substrate 1 (IRS1) [130]. Iron depletion by deferoxamine upregulated glucose uptake and insulin signaling in hepatoma cells and rat liver [131]. These results suggest that iron overload may contribute to insulin resistance in NAFLD. Furthermore, iron overload might also be involved in the disturbance of lipid metabolism in NAFLD [132, 133]. The comparison of iron overload between ALD and NAFLD is presented in Table 1.

Table 1.

Comparison of iron overload between ALD and NAFLD

Changes of molecules in iron homeostasis

Mechanisms of iron overload

Detrimental effects of iron overload

ALD

Serum iron (+), ferritin (+), TS (+), hepcidin (−)

Hepatic FPN (+); duodenal DMT1 (+), FPN (+)

Increasing iron absorption via suppressing hepcidin expression by inducing oxidative stress and EPO production

Increasing TfR expression possibly by activating IRPs

Acting on intestinal SIRT1-LCN2 signaling

Promoting ethanol-induced oxidative lipid, protein and DNA damage; inducing hepatocyte ferroptosis; triggering the activation of KCs and inflammation; inducing HSCs’ activation and progression of fibrosis

NAFLD

Serum ferritin (+), TS (+), hepcidin (+)

Hepatic FPN (−), TfR (−); duodenal DMT (?), FPN (−)

Increasing iron absorption via activating DMT (?) and ineffective hepatic iron sensing indicated by low HJV expression

Inducing iron retention in liver cells by decreasing FPN expression

Increasing erythrophagocytosis by KCs

Inducing oxidative lipid, protein and DNA damage, endoplasmic reticulum stress, mitochondrial damage, induction of inflammatory and fibrogenic response, and ferroptosis; inducing insulin resistance; disturbing lipid metabolism

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ALD alcoholic liver disease, DMT1 divalent metal transporter 1, EPO erythropoietin, FPN ferroportin, HJV hemojuvelin, HSCs hepatic stellate cells, IRPs iron-regulatory proteins, KCs Kupffer cells, LCN2 lipocalin-2, NAFLD nonalcoholic fatty liver disease, SIRT1 sirtuin1, TfR transferrin receptor, TS transferrin saturation, DMT (?) DMT1 expression was reported to be unchanged or increased

Targeting iron homeostasis for prevention and treatment of ALD

ALD is usually diagnosed at an irreversible advanced stage due to the lack of characterization of the early stages and sensitive biomarkers. Epidemiological studies have demonstrated that only about 30% of heavy drinkers develop advanced ALD, suggesting alcohol dependence is not the prerequisite for the development of ALD [134]. As liver iron overload is a hallmark of ALD, it would be interesting to investigate whether some iron homeostasis-related molecules could serve as biomarkers predicting ALD risks in alcoholics. The diagnostic role of ferritin and transferrin has been evaluated in several studies. Specifically, carbohydrate-deficient transferrin (CDT), defined as the asialo-, monosialo- and disialo-forms of transferrin, has been used as a biomarker for chronic alcohol consumption over 60 g/day [135, 136]. Interestingly, one study showed that the positive rate of CDT in ALD patients (93.4%, 71/79) was significantly higher than that in those with alcoholism (52.7%, 29/55), suggesting CDT might be a useful biomarker for predicting the risks of ALD in alcoholics [19]. In addition, serum CDT levels were found to be useful in the differential diagnosis of ALD and NAFLD, because it was significantly higher in ALD patients than NAFLD patients [20, 137]. Furthermore, the elevation of serum ferritin level (> 200 μg/L) was found in 64 of 111 (58%) ALD patients and 30 of 137 (22%) patients with other liver diseases including autoimmune liver disease and hepatitis C [71]. In addition to the potential roles in the diagnosis of ALD in alcoholics, some studies have proposed that serum ferritin, transferrin, and hepcidin may be promising biomarkers for predicting mortality of severe and advanced ALD. For instance, serum transferrin could predict mortality with performance comparable with the commonly used composite scoring systems in a cohort study that recruited 828 patients with severe AH [75]. Serum ferritin level was found to be correlated to inflammatory cytokines, while TS was related to liver function impairment and the survival of patients with alcoholic cirrhosis [138]. Another study suggested that low-serum hepcidin levels were associated with poor long-term survival in alcoholic cirrhosis [139]. These studies suggest that special attention is needed for ALD patients with higher transferrin and ferritin, and lower hepcidin. Anyway, well-designed studies with large sample size are needed to confirm the roles of components in iron homeostasis in diagnosis and prognosis of ALD.

Several targets may be considered for restoring iron homeostasis in ALD. The first group is iron chelators. Several iron chelators are now used clinically including deferasirox, deferoxamine, and deferiprone, which have been tested for the treatment of iron-related diseases such as transfusion-dependent hemoglobinopathies in clinical trials [140, 141]. Among them, deferiprone has been demonstrated to reduce hepatic iron overload, lipid peroxidation, and fat accumulation in chronically ethanol-fed rats [142]. In addition, a novel iron chelator M30 significantly suppressed ethanol-induced apoptosis, oxidative stress, inflammatory cytokines secretion, and the activation of the NLRP3 inflammasome [143]. It is noteworthy that one study showed that a long-acting parenteral iron chelator, hydroxyethyl starch-deferoxamine, failed to protect against ethanol-induced liver injury in rats, which was thought to be due to the lower bioavailability [144]. The efficacy of iron chelators in ALD treatment is needed to be further validated in animal studies, which would provide evidence for clinical trials. Secondly, downregulation of hepcidin has been demonstrated to be the contributor to ethanol-induced iron imbalance, and thus, hepcidin would be a possible target to restore ethanol-disturbed iron homeostasis. Hepcidin exhibited protection against LPS-induced liver and kidney injury [145, 146]. A short lipophilic hepcidin mimic called mini-hepcidin (PR65) significantly reduced liver and heart iron levels in a mouse model of iron overload [147, 148]. However, whether supplementation with hepcidin could ameliorate ethanol-induced liver injury remains to be investigated. Third, oxidative stress and iron-related ferroptosis have been suggested to be the downstream events leading to liver damage, suggesting that antioxidants and ferroptosis inhibitors may possess hepatoprotection against ALD. Indeed, various types of antioxidants exert protection against ALD in various animal models. Ferrostatin-1 significantly ameliorated liver injury that was induced by overdosed alcohol both in vitro and in vivo [94]. However, available clinical trials found that antioxidants were not more effective than placebo [149–151]. Lastly, some natural compounds including flavonoids have been demonstrated to protect against ALD by maintaining iron balance. For instance, quercetin could attenuate ethanol-induced liver damage by acting as an iron-chelating antioxidant [152, 153]. Another flavonoid, baicalin, had been demonstrated to ameliorate iron overload-induced mouse liver injury [154, 155], and thus may also have protection against ALD. Screening the natural compounds may identify some hepaprotective iron-regulating bioactive compounds.

Conclusion

Iron overload is a common hallmark of ALD and may be one of the synergistic factors in the development of ALD. It has been well documented that ethanol exposure could disturb iron homeostasis by downregulating hepcidin expression. However, ethanol may also upregulate the expression of TfR possibly by activating IRPs, while the roles of nonparenchymal cells and extrahepatic tissues remain to be elucidated. Nevertheless, iron overload has been demonstrated to promote the progression of ALD via inducing oxidative stress, triggering ferroptosis of hepatocytes, and promoting the activation of KCs and HSCs. Importantly, some previous studies have demonstrated that the hepatoprotective effects of many compounds against ALD were accompanied by the restoration of iron homeostasis. In addition, specifically, iron chelators and ferroptosis inhibitors were demonstrated to protect against ALD. Results of these studies suggest that targeting iron homeostasis may represent a promising strategy for the prevention and treatment of ALD.

Although the iron overload has been well documented and the underlying mechanisms have been identified, a few studies have investigated the efficiency of restoring iron homeostasis in suppressing the development of ALD. Iron chelators were found to be efficient in ALD animal studies [142, 143], but not tested in clinical trials. The role of hepcidin supplementation in ALD remains unclear, although hepcidin exhibited protection against LPS-induced liver and kidney injury [145, 146]. Ferrostatin-1, a ferroptosis inhibitor, significantly ameliorated ethanol-induced liver injury induced by overdosed alcohol both in vitro and in vivo [94]. Results of these studies have provided preliminary evidence for the efficiency of maintaining iron balance in the treatment of ALD. Well-designed animal experiments and clinical trials are needed to evaluate the efficiency of these compounds.

Abbreviations

ALD: Alcoholic liver disease
BMDM: Bone marrow-derived macrophage
BMP: Bone morphogenetic protein
CDT: Carbohydrate-deficient transferrin
C/EBPα: CCAAT/enhancer-binding protein α
CP: Ceruloplasmin
DAMPs: Damage-associated molecular patterns
DcytB: Duodenal cytochrome b
DMT1: Divalent metal transporter-1
EGF: Epidermal growth factor
EPO: Erythropoietin
ERFE: Erythroferrone
FPN: Ferroportin
GLUT4: Glucose transporter 4
GPX4: Glutathione peroxidase 4
GSH: Glutathione
HCP1: Heme carrier protein-1
HIFs: Hypoxia-inducible factors
HJV: Hemojuvelin
HO1: Heme oxygenase 1
HSCs: Hepatic stellate cells
HGF: Hepatocyte growth factor
4-HNE: 4-Hydroxy-2-nonenal
IL6: Interleukin 6
IL1β: Interleukin 1β
IL22: Interleukin 22
IRE: Iron-responsive element
IRPs: Iron regulatory proteins
IRS1: Insulin receptor substrate 1
JAK2: Janus kinase 2
KCs: Kupffer cells
LCN2: Lipocalin-2
LPS: Lipopolysaccharide
NAC: N-Acetylcysteine
NAFLD: Nonalcoholic fatty liver disease
NASH: Nonalcoholic steatohepatitis
NF-κB: Nuclear factor-κB
NLRP3: NOD-like receptor family pyrin domain containing 3
NRF2: Nuclear factor erythroid 2-related factor 2
PDGFRβ: Platelet-derived growth factor receptor β
ROS: Reactive oxygen species
SIRT1: Sirtuin1
αSMA: Smooth muscle α-actin
STAT3: Signal transducers and activators of transcription 3
TS: Transferrin saturation
TfR: Transferrin receptor
TNFα: Tumor necrosis factor α

Author contributions

TZ conceived the concept of the manuscript. L-XL, F-FG, and HL reviewed the literature and wrote the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81872653 and No. 82073585).

Availability of data and materials

All data relevant to this review are included in the text, references, and figures.

Declarations

Conflict of interests

The authors declare no competing interests.

Ethical approval and consent to participate

Not applicable.

Consent for publication

All the authors have read the manuscript and agreed to give their consent for the publication in cellular and molecular life science.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

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Data Availability Statement

All data relevant to this review are included in the text, references, and figures.

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PERMALINK

Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets

Long-Xia Li

Fang-Fang Guo

Hong Liu

Tao Zeng

Abstract

Introduction

Iron homeostasis: metabolism and regulators

Iron absorption, recycling, and storage

Fig. 1.

Regulation of iron homeostasis

Ethanol-induced iron overload and the underlying mechanisms

Iron overload in ALD

The molecular mechanism of ethanol-induced iron overload in the liver

Fig. 2.

Detrimental effects of iron overload in the liver

Fig. 3.

Comparison of iron overload between ALD and NAFLD

Table 1.

Targeting iron homeostasis for prevention and treatment of ALD

Conclusion

Abbreviations

Author contributions

Funding

Availability of data and materials

Declarations

Conflict of interests

Ethical approval and consent to participate

Consent for publication

Footnotes

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets

Long-Xia Li

Fang-Fang Guo

Hong Liu

Tao Zeng

Abstract

Introduction

Iron homeostasis: metabolism and regulators

Iron absorption, recycling, and storage

Fig. 1.

Regulation of iron homeostasis

Ethanol-induced iron overload and the underlying mechanisms

Iron overload in ALD

The molecular mechanism of ethanol-induced iron overload in the liver

Fig. 2.

Detrimental effects of iron overload in the liver

Fig. 3.

Comparison of iron overload between ALD and NAFLD

Table 1.

Targeting iron homeostasis for prevention and treatment of ALD

Conclusion

Abbreviations

Author contributions

Funding

Availability of data and materials

Declarations

Conflict of interests

Ethical approval and consent to participate

Consent for publication

Footnotes

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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