Ritonavir-induced lipoatrophy and dyslipidaemia is reversed by the anti-inflammatory drug leflunomide in a PPAR-γ-dependent manner.
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.
Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, University of Perugia, S. Andrea delle Fratte, Perugia, Italy. andrea.mencarelli@unipg.it
Andrea
A
Mencarelli
Daniela
D
Francisci
Barbara
B
Renga
Claudio
C
D'Amore
Sabrina
S
Cipriani
Flavia
F
Basile
Elisabetta
E
Schiaroli
Franco
F
Baldelli
Stefano
S
Fiorucci
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D050171:Dyslipidemias / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D004822:Epididymis; D005234:Fatty Liver / Q000188:drug therapy / Q000517:prevention & control; D017320:HIV Protease Inhibitors / Q000009:adverse effects; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D000077339:Leflunomide; D008060:Lipodystrophy / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017320:HIV Protease Inhibitors; D007555:Isoxazoles; D047495:PPAR gamma; D000077339:Leflunomide; D019438:Ritonavir