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Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease

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Iron is an essential metal element whose bioavailability is tightly regulated. Under normal conditions, systemic and cellular iron homeostases are synchronized for optimal function, based on the needs of each system. During metabolic dysfunction, this synchrony is lost, and markers of systemic iron homeostasis are no longer coupled to the iron status of key metabolic organs such as the liver and adipose tissue. The effects of dysmetabolic iron overload syndrome in the liver have been tied to hepatic insulin resistance, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. While the existence of a relationship between iron dysregulation and metabolic dysfunction has long been acknowledged, identifying correlative relationships is complicated by the prognostic reliance on systemic measures of iron homeostasis. What is lacking and perhaps more informative is an understanding of how cellular iron homeostasis changes with metabolic dysfunction. This article explores bidirectional relationships between different proteins involved in iron homeostasis and metabolic dysfunction in the liver. © 2022 American Physiological Society. Compr Physiol 12:3641‐3663, 2022.

Figure 1. Figure 1. Graphical abstract of the objective of this article.
Figure 2. Figure 2. The mechanism of the IRE/IRP system for cellular regulation of iron uptake, storage, and export proteins in conditions of iron deficiency and excess. IRE, iron response element; IRP, iron response protein. Adapted from Wilkinson N and Pantopoulos K, 2014 209.
Figure 3. Figure 3. Role of Tf and TfR under normal conditions (in blue panel) and dysregulations observed in patients with DIOS (in red panel) and their associations with hyperglycemia and hyperinsulinemia. Tf, transferrin; TfR, transferrin receptor; DIOS, dysmetabolic iron overload syndrome. Partially adapted from Gammella E, et al., 2017 80.
Figure 4. Figure 4. Normal pleiotropic roles of LRP1 shown (blue panels). How LRP1 is regulated during DIOS and whether dysregulation of its iron handling functions affects the other roles is unknown. LRP1, low‐density lipoprotein receptor‐related protein‐1; DIOS, dysmetabolic iron overload syndrome. Adapted, with permission, from Griffiths S, et al., 2020 85.
Figure 5. Figure 5. Normal function of CD163 in scavenging hemoglobin/haptoglobin bound iron (in blue panel). Observations of increased expression of soluble forms of CD163 in DIOS (in red panel). CD163, cluster of differentiation 163; DIOS, dysmetabolic iron overload syndrome. Partially adapted from Moestrup SK and Møller HJ, 2004 139.
Figure 6. Figure 6. Normal role of HO‐1. Observed paradoxical role of HO‐1 in glucose homeostasis and role in lipid homeostasis in patients with diabetes and NAFLD respectively (red panel). HO‐1, heme oxygenase‐1; OXPHOS, oxidative phosphorylation; NAFLD, nonalcoholic liver fatty disease. Partially adapted from Canesin G, et al., 2020 29.
Figure 7. Figure 7. Fpn exports iron out of the cell and is normally regulated by hepcidin which tags Fpn for ubiquitin‐mediated degradation. During DIOS (red panels), hepcidin levels increase causing iron overload in tissues. In obese animals with mutations in Fpn ROS‐mediated lipotoxicity and mitochondrial dysfunction occur, but at the same time, anti‐inflammatory and antioxidant processes increase. MT, mitochondrial; Fpn, ferroportin; DIOS, dysmetabolic iron overload syndrome; ROS, reactive oxygen species.

Figure 1. Graphical abstract of the objective of this article.

Figure 2. The mechanism of the IRE/IRP system for cellular regulation of iron uptake, storage, and export proteins in conditions of iron deficiency and excess. IRE, iron response element; IRP, iron response protein. Adapted from Wilkinson N and Pantopoulos K, 2014 209.

Figure 3. Role of Tf and TfR under normal conditions (in blue panel) and dysregulations observed in patients with DIOS (in red panel) and their associations with hyperglycemia and hyperinsulinemia. Tf, transferrin; TfR, transferrin receptor; DIOS, dysmetabolic iron overload syndrome. Partially adapted from Gammella E, et al., 2017 80.

Figure 4. Normal pleiotropic roles of LRP1 shown (blue panels). How LRP1 is regulated during DIOS and whether dysregulation of its iron handling functions affects the other roles is unknown. LRP1, low‐density lipoprotein receptor‐related protein‐1; DIOS, dysmetabolic iron overload syndrome. Adapted, with permission, from Griffiths S, et al., 2020 85.

Figure 5. Normal function of CD163 in scavenging hemoglobin/haptoglobin bound iron (in blue panel). Observations of increased expression of soluble forms of CD163 in DIOS (in red panel). CD163, cluster of differentiation 163; DIOS, dysmetabolic iron overload syndrome. Partially adapted from Moestrup SK and Møller HJ, 2004 139.

Figure 6. Normal role of HO‐1. Observed paradoxical role of HO‐1 in glucose homeostasis and role in lipid homeostasis in patients with diabetes and NAFLD respectively (red panel). HO‐1, heme oxygenase‐1; OXPHOS, oxidative phosphorylation; NAFLD, nonalcoholic liver fatty disease. Partially adapted from Canesin G, et al., 2020 29.

Figure 7. Fpn exports iron out of the cell and is normally regulated by hepcidin which tags Fpn for ubiquitin‐mediated degradation. During DIOS (red panels), hepcidin levels increase causing iron overload in tissues. In obese animals with mutations in Fpn ROS‐mediated lipotoxicity and mitochondrial dysfunction occur, but at the same time, anti‐inflammatory and antioxidant processes increase. MT, mitochondrial; Fpn, ferroportin; DIOS, dysmetabolic iron overload syndrome; ROS, reactive oxygen species.
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How to Cite

Magdalene Ameka, Alyssa H. Hasty. Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease. Compr Physiol 2022, 12: 3641-3663. doi: 10.1002/cphy.c210039