Research Article Details
| Article ID: | A24479 |
| PMID: | 22854109 |
| Source: | Metabolism |
| Title: | 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. |
| Abstract: | OBJECTIVE: 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. MATERIALS/METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. |
| DOI: | 10.1016/j.metabol.2012.06.008 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |