Sunday, May 11, 2025
5/11/2025
Mechanistic insights into the crosstalk between iron metabolism and diabetes - In the United States 10.5% of the population has diabetes, accounting for over 3% of deaths and costs an estimated $327 billion in 2017. Iron overload is a strong risk factor both the incidence of diabetes and the progression of diabetic complications. Reduction of iron content improves diabetic complications and insulin sensitivity. Therefore, a better understanding of iron metabolism in diabetes as well as the precise mechanisms underlying the detrimental role of iron could identify novel treatment modalities for diabetic control. Our published work and new preliminary data have shown that hyperactive protein kinase Cα (PKCα) signaling associated with diabetes promotes dietary iron absorption by up-regulating iron importer divalent metal transporter 1 (DMT1) and exporter ferroportin (Fpn). The importance of PKCα in the regulation of intestinal iron absorption is supported by in vivo findings in PKCα-/- mice showing decreased Fpn expression and increased iron retention in intestinal epithelium as well as diminished liver and serum iron. Liver is the primary site of iron deposition, and plays a major role in systemic glucose homeostasis. We further observed that iron loading exacerbates diabetes-associated liver injury and inflammation through induction of hepatocyte ferroptosis. We hypothesize that PKCα is an important regulator of the crosstalk between diabetes and iron metabolism by mediating hyperglycemia-induced iron loading and exacerbated liver injury. We will utilize multiple genetically engineered mouse models, cultured intestinal epithelial cells, and intestinal biopsies of diabetic patients to address the following interconnected specific aims. Aim 1: To understand the mechanisms by which hyperglycemia-PKCα axis increases intestinal iron import. We will demonstrate that cereblon, a substrate receptor of E3 ubiquitin ligase, binds and mediates the ubiquitination of intestinal DMT1. Hyperactive PKCα inhibits DMT1-cereblon interaction and the ubiquitination/internalization of DMT1, enhancing membrane expression of DMT1 and iron uptake. Aim 2: To understand the mechanism by which hyperactive PKCα up-regulates Fpn stability and iron export in the intestine. We will identify a novel mechanism underlying the regulation of Fpn stability, wherein diabetes-induced activation of PKCα increases Fpn phosphorylation and acetylation counteracting hepcidin-induced ubiquitination and degradation of Fpn. Diabetic up-regulation of Fpn and its PKCα dependency will be also examined using duodenal biopsies of diabetic patients. Aim 3: To identify the mechanism by which iron loading exacerbates diabetic liver injury. We will establish that iron loading, in the context of diabetes-induced impairment in autophagy, induces hepatocytes ferroptosis as a novel mechanism exacerbating liver injury in diabetes. We will further test if the loss-of-function of PKCα alleviates liver injury through reduction of hepatic iron content. These studies will highlight the important role of PKCα in diabetes-induced iron loading and tissue injury as well as the precise molecular mechanisms, laying the foundation for the development of novel treatment modalities in diabetic control.
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