Research Article Details
| Article ID: | A27065 |
| PMID: | 19230890 |
| Source: | Atherosclerosis |
| Title: | Losartan reduces liver expression of plasminogen activator inhibitor-1 (PAI-1) in a high fat-induced rat nonalcoholic fatty liver disease model. |
| Abstract: | OBJECTIVE: To evaluate the effect of losartan-an angiotensin II type 1 receptor (AT1R) antagonist- and telmisartan-an AT1R blocker with insulin-sensitizing properties-, on the hepatic expression of plasminogen activator inhibitor-1 (PAI-1) in a rat model of nonalcoholic fatty liver disease (NAFLD). METHODS: Rats were given a high-fat diet (HFD) for 8 weeks and after this period were randomly divided into 3 groups. For 12 weeks along with the same access to HFD, one group (9 rats) received losartan and another group received telmisartan (10 rats), both at 10mg/kg intraperitoneally (ip) every 24h. The third group (8 rats) received saline ip along with the HFD. Finally, a control group (6 rats) was fed with standard chow diet for 20 weeks. RESULTS: Fatty liver was reverted by both losartan and telmisartan. Both drugs had beneficial effects on insulin resistance, reaching statistical significance in telmisartan group. Expression of hepatic mRNA of PAI-1 showed a 42% decrease in losartan-treated rats in comparison with both HFD group and telmisartan-treated rats. To further evaluate this differential effect on PAI-1 expression, we explored the effect of the drugs on liver expression of TNFalpha, PEPCK-C and PPARalpha, and no significant differences were observed. CONCLUSION: These results indicate that AT1R blockers could be eligible drugs for reducing hepatic lipid accumulation in patients with NAFLD. However, only 12 weeks of losartan treatment strongly reduced hepatic PAI-1 gene expression. These differences could provide even more effective options for preventing fatty liver disease and its cardiovascular complications. |
| DOI: | 10.1016/j.atherosclerosis.2009.01.026 |
| 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 |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T03 | Peroxisome proliferator-activated receptor alpha | PPARA | agonist | Nuclear hormone receptor | Q07869 | PPARA_HUMAN | Details |
| T23 | Type-1 angiotensin II receptor | AGTR1 | antagonist | GPCR | P30556 | AGTR1_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 |
| I07 | 1936 | Arteriosclerosis | Build-up of fatty material and calcium deposition in the arterial wall resulting in partial or complete occlusion of the arterial lumen.https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C35768 | disease of anatomical entity/cardiovascular system disease/ vascular disease/ artery disease | 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 |
| D360 | Telmisartan | Chemical drug | DB00966 | PPARG partial agonist | Improve insulin resistance | Under clinical trials | Details |
| D209 | Losartan | Chemical drug | DB00678 | AGTR1 antagonist&binder | Anti-fibrosis | 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 |