Impaired ferritinophagy flux induced by high fat diet mediates hepatic insulin resistance via endoplasmic reticulum stress

Although iron disequilibrium has been observed frequently in high-fat diet (HFD) related Insulin resistance (IR) the exact mechanism still obscure. Herein, we explore the potential mechanism, focusing on hepatic ferritinophagy flow. Male C57/6J mice were administered with HFD or low-fat diet (LFD) for 10 weeks, and HepG2 cells were treated with palmitate (PA, 200 mM) for 24 h. HFD led to abnormal hepatic steatosis and decline p-AKT and p-GSK3β by 67.1% and 66.3%, respectively. Also, not only decreased iron level but increased endoplasmic reticulum stress (ERS) were observed in the liver of HFD mice and that both them impaired glucose uptake and reduced the expression of p-AKT. However, ferric ammonium citrate (FAC) supplementation improved hepatic IR, as well as ERS. What's more, HFD/PA depleted the labile iron pool (LIP), accumulated p62 and disturbed the expression of nuclear receptor coactivator 4 (NCOA4) and ferritin. While NCOA4 overexpression or rapamycin improved the ERS and impaired glucose uptake in PA incubated HepG2 cells, which was abolished by NCOA4 knockdown or bafilomycin A1. Taken together, these findings suggest that HFD could restrict ferritinophagy flux and interfere with iron metabolism, which resulting in hepatic IR via ERS.