Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target

Summary 

The dysmetabolic iron overload syndrome (DIOS) is now a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. The pathogenesis is related to altered regulation of iron transport associated with steatosis, insulin resistance, and subclinical inflammation, often in the presence of predisposing genetic factors. Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage.

Based on these premises, the association among DIOS, metabolic syndrome, and NAFLD is being investigated as a new risk factor to predict the development of overt cardiovascular and hepatic diseases, and possibly hepatocellular carcinoma, but most importantly, represents also a treatable condition. Indeed, iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Additional studies are warranted to evaluate the potential of iron reductive therapy on hard clinical outcomes in patients with DIOS.

Abbreviations: DIOS, dysmetabolic iron overload syndrome, NAFLD, nonalcoholic fatty liver disease, HHC, hereditary hemochromatosis, MetS, metabolic syndrome, ID, iron depletion, IR, insulin resistance, NASH, nonalcoholic steatohepatitis, HFD, high-fat diet, FFAs, free fatty acids, ER, endoplasmic reticulum, T2D, type 2 diabetes, PCOS, polycystic ovary syndrome, Cp, ceruloplasmin, Fp-1, ferroportin-1, HFE, hemochromatosis gene, AAT, alpha1-antitrypsin, ROS, reactive oxygen species, HO-1, heme oxygenase-1, RBP4, retinol binding protein-4, HSCs, hepatic stellate cells, 8-oxodG, 7,8-dihydro-8-oxo-2′ deoxyguanosine, MCD, methionine choline deficient diet, InsR, insulin receptor

Keywords: Iron, Insulin resistance, Nonalcoholic fatty liver disease, Metabolic syndrome, Vascular damage, Hereditary hemochromatosis, Nonalcoholic steatohepatitis, Oxidative stress