Hepatocyte Nuclear Factor 4α Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver.

Iron is an essential element in biological systems, but excess iron promotes the formation of reactive oxygen species, resulting in cellular toxicity. Several iron-related genes are highly expressed in the liver, a tissue in which hepatocyte nuclear factor 4α (HNF4α) plays a critical role in controlling gene expression. Therefore, the role of hepatic HNF4α in iron homeostasis was examined using liver-specific HNF4α-null mice (Hnf4a(ΔH) mice). Hnf4a(ΔH) mice exhibit hypoferremia and a significant change in hepatic gene expression. Notably, the expression of transferrin receptor 2 (Tfr2) mRNA was markedly decreased in Hnf4a(ΔH) mice. Promoter analysis of the Tfr2 gene showed that the basal promoter was located at a GC-rich region upstream of the transcription start site, a region that can be transactivated in an HNF4α-independent manner. HNF4α-dependent expression of Tfr2 was mediated by a proximal promoter containing two HNF4α-binding sites located between the transcription start site and the translation start site. Both the GC-rich region of the basal promoter and the HNF4α-binding sites were required for maximal transactivation. Moreover, siRNA knockdown of HNF4α suppressed TFR2 expression in human HCC cells. These results suggest that Tfr2 is a novel target gene for HNF4α, and hepatic HNF4α plays a critical role in iron homeostasis.

Clinical Prediction Rule for Declines in Activities of Daily Living at 6 Months After Surgery for Hip Fracture Repair.

OBJECTIVES: To develop and assess a clinical prediction rule (CPR) to predict declines in activities of daily living (ADL) at 6 months after surgery for hip fracture repair. DESIGN: Prospective, cohort study. SETTING: From hospital to home. PARTICIPANTS: Patients (N=104) with hip fractures after surgery. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: ADL were assessed using the Barthel Index at 6 months after surgery. RESULTS: At 6 months after surgery, 86 patients (82.6%) were known to be alive, 1 patient (1.0%) had died, and 17 (16.3%) were lost to follow-up. Thirty-two patients (37.2%) did not recover their ADL at 6 months after surgery to levels before fracture. The classification and regression trees methodology was used to develop 2 models to predict a decline in ADL: (1) model 1 included age, type of fracture, and care level before fracture (sensitivity=75.0%, specificity=81.5%, positive predictive value=70.6%, positive likelihood ratio=4.050); and (2) model 2 included the degree of independence 2 weeks postsurgery for ADL chair transfer, ADL ambulation, and age (sensitivity=65.6%, specificity=87.0%, positive predictive value=75.0%, positive likelihood ratio=5.063). The areas under the receiver operating characteristic curves of both CPR models were .825 (95% confidential interval, .728-.923) and .790 (95% confidence interval, .683-.897), respectively. CONCLUSIONS: CPRs with moderate accuracy were developed to predict declines in ADL at 6 months after surgery for hip fracture repair.