The Role of the Liver in Iron Homeostasis and What Goes Wrong?

Iron is an essential mineral that is vital for growth development, normal cellular function, synthesis of hormones and connective tissue, and most importantly, serves as a component of hemoglobin to carry oxygen to body tissues. The body finely regulates the amount of circulating and stored iron within the body to maintain concentration levels within range for optimal physiologic function. Without iron, the ability for cells to participate in electron transport and energy metabolism decreases. Furthermore, hemoglobin synthesis is altered, which leads to anemia and decreased oxygen delivery to tissue. Problems arise when there is too little or too much iron. This review explores the role of the liver in iron physiology, iron overload and discusses the most common causes of primary and secondary hepatic iron overload.

Determination of Non-Invasive Biomarkers for the Assessment of Fibrosis, Steatosis and Hepatic Iron Overload by MR Image Analysis. A Pilot Study

The reference diagnostic test of fibrosis, steatosis, and hepatic iron overload is liver biopsy, a clear invasive procedure. The main objective of this work was to propose HSA, or human serum albumin, as a biomarker for the assessment of fibrosis and to study non-invasive biomarkers for the assessment of steatosis and hepatic iron overload by means of an MR image acquisition protocol. It was performed on a set of eight subjects to determine fibrosis, steatosis, and hepatic iron overload with four different MRI sequences. We calibrated longitudinal relaxation times (T1 [ms]) with seven human serum albumin (HSA [%]) phantoms, and we studied the relationship between them as this protein is synthesized by the liver, and its concentration decreases in advanced fibrosis. Steatosis was calculated by means of the fat fraction (FF [%]) between fat and water liver signals in “fat-only images” (the subtraction of in-phase [IP] images and out-of-phase [OOP] images) and in “water-only images” (the addition of IP and OOP images). Liver iron concentration (LIC [µmol/g]) was obtained by the transverse relaxation time (T2* [ms]) using Gandon’s method with multiple echo times (TE) in T2-weighted IP and OOP images. The preliminary results showed that there is an inverse relationship (r = −0.9662) between the T1 relaxation times (ms) and HSA concentrations (%). Steatosis was determined with FF > 6.4% and when the liver signal was greater than the paravertebral muscles signal, and thus, the liver appeared hyperintense in fat-only images. Hepatic iron overload was detected with LIC > 36 µmol/g, and in these cases, the liver signal was smaller than the paravertebral muscles signal, and thus, the liver behaved as hypointense in IP images.

Orphan Nuclear Receptor ERRγ Is a Transcriptional Regulator of CB1 Receptor-Mediated TFR2 Gene Expression in Hepatocytes

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2′-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.