Research Article Details
| Article ID: | A26276 |
| PMID: | 20801629 |
| Source: | J Nutr Biochem |
| Title: | Role of tumor necrosis factor α (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. |
| Abstract: | Tumor necrosis factor α (TNFα) is known to be involved in dysregulation of hepatic lipid metabolism and insulin signaling. However, whether TNFα also plays a casual role in the onset of fructose-induced nonalcoholic fatty liver disease (NAFLD) has not yet been determined. Therefore, wild-type and TNFα receptor 1 (TNFR1)-/- mice were fed with either 30% fructose solution or plain tap water. Hepatic triglycerides, markers of inflammation and ATP concentration as well as plasma ALT levels were determined. Hepatic PAI-1, SREBP-1, FAS mRNA expression was assessed by real-time RT-PCR. Furthermore, lipid peroxidation and indices of insulin resistance were determined in liver tissue and plasma. In comparison to water controls, chronic intake of 30% fructose solution caused a significant ∼5-fold increase in triglyceride accumulation and neutrophil infiltration in livers of wild-type mice and a ∼8-fold increase in plasma ALT levels. In TNFR1-/- mice, hepatic steatosis was attenuated and neutrophil infiltration in the liver as well as plasma ALT levels was similar to water controls. The protective effect of the TNFR1 deletion against the onset of fructose-induced steatosis was associated with increased phospho AMPK and Akt levels, decreased SREBP-1 and FAS expression in the liver and decreased RBP4 plasma levels, whereas hepatic lipid peroxidation, iNOS protein and ATP levels were similar between wild-type and TNFR1-/- mice fed fructose. Taken together, these data suggest that TNFα plays a casual role in the onset of fructose-induced liver damage as well as insulin resistance in mice through signaling cascades downstream of TNFR1. |
| DOI: | 10.1016/j.jnutbio.2010.04.007 |
| 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 |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | 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 | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D142 | Fructose | Chemical drug | DB04173 | -- | Intravenous nutrition drug | Under clinical trials | Details |