Paying the Iron Price: Liver Iron Homeostasis and Metabolic Disease

Abstract

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.

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

“…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 ].…”

Adipose knockout of H-ferritin improves energy metabolism in mice

“…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 ].…”