Ferroportin Expression in Adipocytes Does Not Contribute to Iron Homeostasis or Metabolic Responses to a High Calorie Diet

Abstract

Background & AimsIron has an increasingly recognized role in the regulation of adipose tissue function, including the expression of adipokines involved in the pathogenesis of nonalcoholic fatty liver disease. The cellular iron exporter, ferroportin, has been proposed as being a key determinant of adipocyte iron homeostasis.MethodsWe studied an adipocyte-specific ferroportin (Fpn1) knockout mouse model, using an Adipoq-Cre recombinase driven Fpn1 deletion and fed mice according to the fast food diet model of nonalcoholic steatohepatitis.ResultsWe showed successful selective deletion of Fpn1 in adipocytes, but found that this did not lead to increased adipocyte iron stores as measured by atomic absorption spectroscopy or histologically quantified iron granules after staining with 3,3’-diaminobenzidine–enhanced Perls’ stain. Mice with adipocyte-specific Fpn1 deletion did not show dysregulation of adiponectin, leptin, resistin, or retinol-binding protein-4 expression. Similarly, adipocyte-specific Fpn1 deletion did not affect insulin sensitivity during hyperinsulinemic–euglycemic clamp studies or lead to histologic evidence of increased liver injury. We have shown, however, that the fast food diet model of nonalcoholic steatohepatitis generates an increase in adipose tissue macrophage infiltration with crown-like structures, as seen in human beings, further validating the utility of this model.ConclusionsFerroportin may not be a key determinant of adipocyte iron homeostasis in this knockout model. Further studies are needed to determine the mechanisms of iron metabolism in adipocytes and adipose tissue.

Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload

“…Moreover, this finding demonstrates in vivo that a liverderived endocrine signal plays an essential role in the activity of intestinal enzymes that regulate HIF-2α. Numerous reports have recently begun to characterize the function of FPN in organs that do not play a role in maintaining systemic iron homeostasis (16,43,44). It will therefore be vital to determine whether FPNmediated iron efflux directly regulates iron-dependent proteins A/C (3A6-4C11, Active Motif), HIF-2α (BL-95-1A2, Bethyl), and HIF-1α (179483, Abcam) for human lysates; and actin (60008-1, Proteintech) for mouse tissue and rat cell lysates.…”

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Similarly, Gabrielsen et al reported that adipocyte-targeted deletion of Fpn using the aP2-Cre mouse model triggers insulin resistance (121). In contrast, another study showed that adipocyte-specific Fpn deletion using the Adipoq-Cre recombinase mouse line does not cause a whole-body insulin-resistant phenotype, and feeding Adipoq-Cre Fpn-knockout mice a Western-type diet (supplemented with high-fructose corn syrup in drinking water, 42 g/L) did not increase adipocyte iron content compared with animals on a control diet (124). Notably, however, the aP2 promoter is also expressed in Mɸs (125) and neurons (126), suggesting that the discrepant phenotype observed by Gabrielsen et al (121) may be related to impaired neural and/or Mɸ iron cycling, although this postulate has not been formally tested.…”

Micronutrients in Nonalcoholic Fatty Liver Disease Pathogenesis

“…Ferroportin is expressed in multiple tissues but the enterocyte ferroportin is considered the major driver of iron hemostasis. 73 Hepcidin, ferroportin, ferritin (the storage form of iron), and iron itself all have been associated with hepatic injury in NAFLD. In patients with NAFLD, genetic mutations and polymorphisms affecting hepcidin’s regulation of ferroportin-mediated iron absorption may result in either increased hepatic iron content (in the case of genetic hemochromatosis) 74 or reduced hepatic iron content (in the case of the VV genotype of the transmembrane protease serine-6 gene).…”