Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease

Ameka, Magdalene; Hasty, Alyssa H.

doi:10.1002/cphy.c210039

Cited by 6 publications

(2 citation statements)

References 209 publications

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“…Systemic hypoferremia is a part of the acute phase response of human infections and likely protects against extracellular infections. Excess iron is stored in the liver, and iron overload is diagnosed in 30% of patients with both non-alcoholic fatty liver disease and the metabolic syndrome [ 125 ].…”

Section: Cellular Mechanisms To Cope With the Energy Crisismentioning

confidence: 99%

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

Fehsel

2023

Biomedicines

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Impaired iron metabolism has been increasingly observed in many diseases, but a deeper, mechanistic understanding of the cellular impact of altered iron metabolism is still lacking. In addition, deficits in neuronal energy metabolism due to reduced glucose import were described for Alzheimer’s disease (AD) and its comorbidities like obesity, depression, cardiovascular disease, and type 2 diabetes mellitus. The aim of this review is to present the molecular link between both observations. Insufficient cellular glucose uptake triggers increased ferritin expression, leading to depletion of the cellular free iron pool and stabilization of the hypoxia-induced factor (HIF) 1α. This transcription factor induces the expression of the glucose transporters (Glut) 1 and 3 and shifts the cellular metabolism towards glycolysis. If this first line of defense is not adequate for sufficient glucose supply, further reduction of the intracellular iron pool affects the enzymes of the mitochondrial electron transport chain and activates the AMP-activated kinase (AMPK). This enzyme triggers the translocation of Glut4 to the plasma membrane as well as the autophagic recycling of cell components in order to mobilize energy resources. Moreover, AMPK activates the autophagic process of ferritinophagy, which provides free iron urgently needed as a cofactor for the synthesis of heme- and iron–sulfur proteins. Excessive activation of this pathway ends in ferroptosis, a special iron-dependent form of cell death, while hampered AMPK activation steadily reduces the iron pools, leading to hypoferremia with iron sequestration in the spleen and liver. Long-lasting iron depletion affects erythropoiesis and results in anemia of chronic disease, a common condition in patients with AD and its comorbidities. Instead of iron supplementation, drugs, diet, or phytochemicals that improve energy supply and cellular glucose uptake should be administered to counteract hypoferremia and anemia of chronic disease.

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Section: Cellular Mechanisms To Cope With the Energy Crisismentioning

confidence: 99%

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

Fehsel

2023

Biomedicines

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“…One important reason for this confusion might be that the already complex connection between iron and energy metabolism is further exacerbated by the fact that both iron and glucose/fat metabolisms are subject to systemic regulation. For example, fat metabolism may be regulated not only by iron in the adipocyte but also by cross-talks with the liver [ 7 ], CNS [ 8 ], and gut [ 9 , 10 ], where iron all exert effects. A hypothetical scenario to illustrate this is that, on the one hand, iron outside of the adipocytes could act in such a way that directly stimulates fat synthesis [ 11 ] or diet intake [ 12 ]; however, on the other hand, iron in the adipocyte could influence oppositely, i.e., increase fat utilization [ 3 , 13 ].…”

Section: Introductionmentioning

confidence: 99%