HIV protease inhibitor ritonavir induces lipoatrophy in male mice.
We investigated the effects of the HIV protease inhibitor ritonavir on body composition, serum lipids, and gene expression in C57BL/6 mice. Dual-energy X-ray absorptiometry measurements in ritonavir-treated male mice revealed whole-body lipoatrophy. In female mice fat reduction was restricted to the gonadal depot. A histopathological analysis showed no visible abnormalities in liver or adipose tissue from ritonavir-treated mice, although adipocytes were significantly smaller in diameter. Serum triglyceride levels were increased in ritonavir-treated male mice. Ritonavir was coadministered with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist gemfibrozil and the PPARgamma agonist rosiglitazone for 8 weeks. Neither drug alleviated the hypertriglyceridemia or lipoatrophy in ritonavir-treated male mice. Rather, gemfibrozil exacerbated the lipoatrophy. Ritonavir reduced basal expression of two PPARalpha target genes in liver, as well as the PPARgamma target gene phosphoenolpyruvate carboxykinase (PEPCK) in adipose tissues. Ritonavir partially inhibited induction of PPAR target genes by gemfibrozil and rosiglitazone. Gemfibrozil induced expression of fatty acid oxidation genes in liver, and this induction was less substantial when ritonavir was coadministered. Similarly, rosiglitazone induced expression of uncoupling protein-1, uncoupling protein-2, and PEPCK in adipose tissues, and this effect was partially inhibited by ritonavir. Thus, the effects of ritonavir on serum triglycerides and body composition may be due, at least in part, to an inhibition of PPAR function.
Goetzman
Eric S
ES
Department of Genetics, University of Alabama at Birmingham, Alabama 35294, USA.
Tian
Liqun
L
Nagy
Tim R
TR
Gower
Barbara A
BA
Schoeb
Trenton R
TR
Elgavish
Ada
A
Acosta
Edward P
EP
Saag
Michael S
MS
Wood
Philip A
PA
D000818:Animals; D005227:Fatty Acids / Q000096:biosynthesis*; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D008060:Lipodystrophy / Q000139:chemically induced* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019438:Ritonavir / Q000009:adverse effects*; D013261:Sterols / Q000096:biosynthesis
D005227:Fatty Acids; D017320:HIV Protease Inhibitors; D013261:Sterols; D019438:Ritonavir