Basic Science| Volume 62, ISSUE 1, P62-69, January 2013

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High-fat, high-fructose diet induces hepatic iron overload via a hepcidin-independent mechanism prior to the onset of liver steatosis and insulin resistance in mice



      Excess iron deposition in tissues leads to increased oxidative stress. The clinical observation that non-alcoholic fatty liver disease (NAFLD) is frequently associated with hepatic iron overload (HIO) indicates that iron-induced oxidative stress may be related to NAFLD pathology. Decreased expression of hepcidin, a hepatic hormone that suppresses dietary iron absorption in the duodenum, is frequently observed in NAFLD patients and has been postulated to be a cause of HIO.


      Because dietary fat and fructose intake play roles in the onset of NAFLD, we fed C57BL/6J mice a high-fat, high-fructose (HFHFr) diet for 16 weeks to study the relationship between hepatic iron content and NAFLD.


      Within 4 weeks after the start of the experiment, the mice exhibited significant increases in hepatic free fatty acid (FFA) content, serum insulin levels, and the homeostasis model assessment of insulin resistance. Interestingly, hepatic iron content and oxidative stress significantly increased with the HFHFr diet 2 weeks earlier than hepatic FFA accumulation and decreased insulin sensitivity. Moreover, hepatic hepcidin expression was significantly downregulated, as is also observed in NAFLD patients, but much later than the onset of HIO.


      Accordingly, our data demonstrated that HIO may have a pathogenic role in the onset of liver steatosis and insulin resistance. Moreover, distinct mechanisms, in addition to hepcidin, may underlie NAFLD-related HIO. These data suggest that the HFHFr diet can be used for establishing a suitable model to study the precise mechanism of HIO in NAFLD patients.


      ALT (alanine aminotransferase), AST (aspartate aminotransferase), FFA (free fatty acid), HFHFr (high-fat, high-fructose diet), HIO (hepatic iron overload), HOMA-IR (homeostasis model assessment of insulin resistance), JNK (c-Jun N-terminal kinase), NAFLD (non-alcoholic fatty liver disease), TG (triglyceride)


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