Targeting PKCα alleviates iron overload in diabetes and hemochromatosis through the inhibition of ferroportin.
Blood
; 144(13): 1433-1444, 2024 Sep 26.
Article
en En
| MEDLINE
| ID: mdl-38861671
ABSTRACT
ABSTRACT Ferroportin (Fpn) is the only iron exporter, playing a crucial role in systemic iron homeostasis. Fpn is negatively regulated by its ligand hepcidin, but other potential regulators in physiological and disease conditions remain poorly understood. Diabetes is a metabolic disorder that develops body iron loading with unknown mechanisms. By using diabetic mouse models and human duodenal specimens, we demonstrated that intestinal Fpn expression was increased in diabetes in a hepcidin-independent manner. Protein kinase C (PKC) is hyperactivated in diabetes. We showed that PKCα was required to sustain baseline Fpn expression and diabetes-induced Fpn upregulation in the enterocytes and macrophages. Knockout of PKCα abolished diabetes-associated iron overload. Mechanistically, activation of PKCα increased the exocytotic trafficking of Fpn and decreased the endocytic trafficking of Fpn in the resting state. Hyperactive PKCα also suppressed hepcidin-induced ubiquitination, internalization, and degradation of Fpn. We further observed that iron loading in the enterocytes and macrophages activated PKCα, acting as a novel mechanism to enhance Fpn-dependent iron efflux. Finally, we demonstrated that the loss-of-function of PKCα and pharmacological inhibition of PKC significantly alleviated hereditary hemochromatosis-associated iron overload. Our study has highlighted, to our knowledge, for the first time, that PKCα is an important positive regulator of Fpn and a new target in the control of iron homeostasis.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sobrecarga de Hierro
/
Proteínas de Transporte de Catión
/
Proteína Quinasa C-alfa
/
Hepcidinas
/
Hemocromatosis
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Blood
Año:
2024
Tipo del documento:
Article