Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis

Abstract

Background and Aims Iron is essential yet also highly chemically reactive and potentially toxic. The mechanisms that allow cells to use iron safely are not clear; defects in iron management are a causative factor in the cell‐death pathway known as ferroptosis. Poly rC binding protein 1 (PCBP1) is a multifunctional protein that serves as a cytosolic iron chaperone, binding and transferring iron to recipient proteins in mammalian cells. Although PCBP1 distributes iron in cells, its role in managing iron in mammalian tissues remains open for study. The liver is highly specialized for iron uptake, utilization, storage, and secretion. Approach and Results Mice lacking PCBP1 in hepatocytes exhibited defects in liver iron homeostasis with low levels of liver iron, reduced activity of iron enzymes, and misregulation of the cell‐autonomous iron regulatory system. These mice spontaneously developed liver disease with hepatic steatosis, inflammation, and degeneration. Transcriptome analysis indicated activation of lipid biosynthetic and oxidative‐stress response pathways, including the antiferroptotic mediator, glutathione peroxidase type 4. Although PCBP1‐deleted livers were iron deficient, dietary iron supplementation did not prevent steatosis; instead, dietary iron restriction and antioxidant therapy with vitamin E prevented liver disease. PCBP1‐deleted hepatocytes exhibited increased labile iron and production of reactive oxygen species (ROS), were hypersensitive to iron and pro‐oxidants, and accumulated oxidatively damaged lipids because of the reactivity of unchaperoned iron. Conclusions Unchaperoned iron in PCBP1‐deleted mouse hepatocytes leads to production of ROS, resulting in lipid peroxidation (LPO) and steatosis in the absence of iron overload. The iron chaperone activity of PCBP1 is therefore critical for limiting the toxicity of cytosolic iron and may be a key factor in preventing the LPO that triggers the ferroptotic cell‐death pathway.

Iron Metabolism in Ferroptosis

“…Paradoxically, hepatocytes lacking PCBP1 show increased redox activity and unchaperoned iron, therefore causing lipid peroxidation (Protchenko et al, 2020). Restricting dietary iron and the supplementing of antioxidant vitamin E can prevent hepatic steatosis associated with ferroptosis (Protchenko et al, 2020). Overall, these findings suggest that PCBP1 plays a complex role in the regulation of ferroptosis-related liver disease.…”

“…Poly(RC) binding proteins 1 has been shown to limit ferroptosis in hepatocytes (Protchenko et al, 2020). Mice lacking Pcbp1 in hepatocytes show defects in iron homeostasis and develop liver disease with hepatic steatosis, inflammation, and degeneration (Protchenko et al, 2020). Transcriptome analysis reveals the activation of lipid biosynthetic and oxidative stress response pathways, including the anti-ferroptotic regulator GPX4.…”

“…Although PCBP1-deleted hepatocytes are iron-deficient, the supplementation of iron dose doesn't inhibit the hepatic steatosis, indicating that hepatic steatosis may not require iron deficiency. Paradoxically, hepatocytes lacking PCBP1 show increased redox activity and unchaperoned iron, therefore causing lipid peroxidation (Protchenko et al, 2020). Restricting dietary iron and the supplementing of antioxidant vitamin E can prevent hepatic steatosis associated with ferroptosis (Protchenko et al, 2020).…”

<p>Association of Metabolic Syndrome and Hyperferritinemia in Patients at Cardiovascular Risk</p>

“…This condition can progress to cirrhosis, and in about 2 to 3% of patients, hepatocellular carcinoma may occur. [39][40][41][42][43][44] For all these reasons, it is crucial to investigate the ferritin concentration and the MS parameters in patients.…”

The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease

“…Subsequent silencing of Tsukushi improved NASH and attenuated the hepatic transcriptional alterations associated with it [ 122 ]. Transcriptomics were also implemented in recent murine models assessing the NAFLD-related role of Poly rC binding protein 1, a cytosolic iron chaperone, whose deficiency exacerbates steatosis and inflammation, increases lipid biosynthesis and oxidative stress pathway expression levels, and is treated via reduced iron intake and vitamin E supplementation [ 123 ]. Lastly, in view of the COVID-19 pandemic, the expression levels of 4 SARS-COV-2 entry proteins were assessed by liver transcriptomics in human and murine NAFLD and NASH cohorts, with no significant changes being detected [ 124 ].…”