Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Abstract

Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxylradicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

“…Indeed, over 100 million people in the United States alone are afflicted with some form of NAFLD, and ∼20 to 30% of NAFLD cases progress to pathological liver inflammation and cirrhosis, which can lead to liver failure or cancer (58,59). The exact disease pathology of NAFLD is insufficiently understood, but clinical evidence has linked inadequate copper supply to the disease extent of NAFLD (23)(24)(25)(26)60). Specifically, endpoint assays of total hepatic copper appear to correlate with increased grades of steatosis and circulating free fatty acids in NAFLD patients relative to control subjects (25).…”

“…This same redox activity also poses a potential danger, requiring highly orchestrated regulation of copper pools to prevent oxidative stress and free radical damage events that are detrimental to health (12)(13)(14)(15)(16)(17)(18). Indeed, genetic disorders that disrupt copper homeostasis lead to severe and lethal conditions such as Menkes and Wilson's diseases (13,19,20), and imbalances in physiological copper levels and tissue miscompartmentalization arising from genetic and/or dietary factors are correlated with cancer, neurodegenerative diseases, and metabolic disorders such as obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

“…The deposition of iron in the liver correlates with disease severity in NAFLD patients [15] . The mechanisms by which excess iron contribute to NAFLD pathogenesis is unclear.…”

“…Iron is also considered as a "second hit" in liver injury [13] and a role for iron has been reported in NASH pathogenesis. Patients with NAFLD/ NASH frequently display elevated serum iron indices and hepatic iron content [14,15] . A strong correlation between hepatic iron content and the level of liver fibrosis in NAFLD/NASH patients has been shown [16][17][18] .…”

Az idült májbetegségek progressziójához vezető folyamatok

“…A csökkent rézszint kapcsolatban áll a NAFLD kórlefolyásában szerepet játszó mitokondriális diszfunkcióval és a lipidperoxidációval. Terápiás célpontot jelenthet a jövőben a diéta szempontjából a rézpótlás, valamint a vasfelhalmozódás és a többletkalória-bevitel csökkentése [31].…”