Long-Term High-Fat Diet Decreases Hepatic Iron Storage Associated with Suppressing TFR2 and ZIP14 Expression in Rats.

High-fat diet-induced obesity is known to disturb hepatic iron metabolism in a time-dependent manner. The mechanism of decreased hepatic iron deposits induced by long-term high-fat diet needs to be further investigated. In this study, 24 6-week-old male Sprague-Dawley rats were given a 16-week high-fat diet and hepatic iron metabolism was examined. High-fat diet feeding considerably decreased hepatic iron contents, enhanced transferrin expression, and reduced the expression of ferritin heavy chain, ferritin light chain, and hepatic iron uptake-related proteins (transferrin receptor 2, TFR2, and ZRT/IRT-like protein 14, ZIP14) in rats. Impaired expression of hepatic TFR2 coincided with DNA hypermethylation on the promoter and repressed expression of transcription factor hepatocyte nuclear factor 4α (HNF4α). miR-181 family expression was markedly increased and verified to regulate Zip14 expression by the dual-luciferase reporter system. Taken together, long-term high-fat diet decreases hepatic iron storage, which is closely linked to inhibition of liver iron transport through the TFR2 and ZIP14-dependent pathway.