Research Article Details
| Article ID: | A52766 |
| PMID: | 22297608 |
| Source: | Antivir Ther |
| Title: | Ritonavir-induced lipoatrophy and dyslipidaemia is reversed by the anti-inflammatory drug leflunomide in a PPAR-γ-dependent manner. |
| Abstract: | BACKGROUND: The complex interplay between viral infection and virus-activated inflammatory pathways with protease inhibitors (PIs) contributes to the increased risk of developing atherosclerosis and coronary artery disease in HIV-infected patients. Leflunomide is an antirheumatic drug whose administration to HIV-1-infected persons effectively decreases T-cell turnover and activation. In this study we have investigated the effects of leflunomide on dyslipidaemia and lipodistrophy induced by ritonavir in rodents. METHODS: Mice were administered ritonavir (5 mg/kg/day) alone or in combination with leflunomide (40 mg/kg/day) for 12 days. Expression of nuclear receptor and lipidogenetic genes was measured in liver and adipose tissues. RESULTS: Administration of the HIV PI ritonavir to mice increased plasma triacylglycerols, free fatty acids and cholesterol levels, and this effect was reverted by cotreatment with leflunomide. Ritonavir administration was associated with reduced epididymal fat/body weight ratio and increased liver content of triacylglycerols content. These effects were reverted by leuflunomide. Histopathology analysis shows that exposure to ritonavir causes inflammation of epididymal fat as demonstrated by dense leukocytes infiltration as well as by increased levels of proinflammatory mediators and reduced expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ). Leflunomide reduced epididymal fat inflammatory-metabolic alteration induced by ritonavir and restored PPAR-γ expression in the epididymal fat. CONCLUSIONS: We have shown that the anti-inflammatory drug leflunomide protects against ritonavir-induced inflammation and dysmetabolism in adipose tissue and might be a promising strategy in the setting of HIV-infected patients at risk for HIV-induced dyslipidaemia. |
| DOI: | 10.3851/IMP2039 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| 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 |
| 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 |
| I06 | 811 | Lipodystrophy | A connective tissue disease that is characterized by marked reduction, absence, and/or the redistribution of adipose tissue. https://www.ncbi.nlm.nih.gov/pubmed/25690482, https://www.ncbi.nlm.nih.gov/pubmed/25833179 | disease of anatomical entity/ musculoskeletal system disease/ connective tissue disease | 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 | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |