Research Article Details
| Article ID: | A45994 |
| PMID: | 21701901 |
| Source: | Hepatol Int |
| Title: | Murine gamma herpes virus 68 infection promotes fatty liver formation and hepatic insulin resistance in C57BL/6J mice. |
| Abstract: | PURPOSE: Murine gamma herpes virus 68 (MHV68) is a naturally occurring mouse pathogen that is homologous to Epstein-Barr virus. This study was designed to determine the correlation between MHV68 infection and lipid accumulation and insulin resistance in livers of C57BL/6J mice, and to explore the underlying mechanisms. METHODS: C57BL/6J mice fed a high fat diet were randomly assigned to receive either MHV68 or phosphate buffered saline treatment. Insulin sensitivities were evaluated by glucose tolerance tests. Serum was analyzed for lipids and cytokines. Liver was taken for histology and lipid analysis. Quantitative RT-PCR and western blotting were used to measure expression of hepatic mammalian target of rapamycin (mTOR), ribosomal S6 kinase 1 (S6K1), insulin receptor substrate-1 (IRS-1), sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FAS), and acetyl CoA carboxylase (ACC). RESULTS: MHV68 infection promoted fatty liver, hypertriglyceridemia, insulin resistance, and hyperinsulinemia in association with elevated inflammatory cytokines. In the livers of MHV68-infected C57BL/6J mice, SREBP1, FAS, ACC levels were increased. MHV68 infection also inhibited total IRS-1 expression and increased serine phosphorylation levels of IRS-1, which is parallel to the over activation of mTOR signaling pathway. Sirolimus, a specific inhibitor of mTOR pathway, inhibited MHV68-induced hepatic expression of serine p-IRS-1, increased total IRS-1 levels and improved MHV68-induced hepatic insulin resistance. CONCLUSION: In C57BL/6J mice, MHV68 infection promotes fatty liver formation and hepatic insulin resistance, which can be ameliorated by sirolimus. |
| DOI: | 10.1007/s12072-011-9283-x |
| 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 |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| 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 |
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| 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 | |
|---|---|---|---|---|---|---|---|
| D612 | Rapamycin | Miscellany | -- | Immunosuppressants; Methylmalonyl CoA mutase stimulants; MTOR protein inhibitors; T lymphocyte inhibitors | -- | Under investigation | Details |
| 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 |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |