Acipimox, an inhibitor of lipolysis, attenuates atherogenesis in LDLR-null mice treated with HIV protease inhibitor ritonavir.
OBJECTIVE
The advent of HIV protease inhibitors has greatly extended the life span of AIDS patients. With an aging HIV(+) population, the cardiometabolic side effects of these drugs are becoming increasingly important clinical concerns. The purpose of this study was to test the hypothesis that inhibition of adipose lipolysis will retard atherogenic lesion development induced by the antiviral protease inhibitors.


RESULTS
LDLR-null mice receiving ritonavir were compared with those receiving ritonavir plus lipolysis inhibitor acipimox or vehicle alone to determine how acipimox would affect ritonavir-induced atherogenesis. Intermittent high-fat high-cholesterol diet was used to facilitate optimal atheromatous lesion development. Drug effects were assessed as changes in aortic lesion score, plasma lipid and lipoprotein profile, body fat mass, and insulin-induced suppression of plasma fatty acid concentrations. Ritonavir increased aortic lesions, in association with decreased body fat mass, impaired antilipolysis action of insulin, and increased proatherogenic plasma lipoproteins. All these adverse effects were attenuated by cotreatment with acipimox.


CONCLUSIONS
Our results provide the first direct evidence that supports the hypothesis that dysregulation of adipose lipolysis is an important contributor to the proatherogenic role of selected HIV protease inhibitors.
Guo
Wen
W
Section of Endocrinology, Boston University School of Medicine, 670 Albany Street, Second Floor, Boston, MA 02118, USA. wguo@bu.edu
Wong
Siu
S
Pudney
Jeffrey
J
Jasuja
Ravi
R
Hua
Ning
N
Jiang
Lan
L
Miller
Andrew
A
Hruz
Paul W
PW
Hamilton
James A
JA
Bhasin
Shalender
S
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D005947:Glucose / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D019438:Ritonavir / Q000008:administration & dosage / Q000633:toxicity*
D017320:HIV Protease Inhibitors; D007328:Insulin; D008055:Lipids; D011719:Pyrazines; D011973:Receptors, LDL; D005947:Glucose; C027696:acipimox; D019438:Ritonavir