Acipimox, an inhibitor of lipolysis, attenuates atherogenesis in LDLR-null mice treated with HIV protease inhibitor ritonavir.

Abstract

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.

METHODS AND 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.

• Authors: Wen Guo, Siu Wong, Jeffrey Pudney, Ravi Jasuja, Ning Hua, Lan Jiang, Andrew Miller, Paul W Hruz, James A Hamilton, Shalender Bhasin
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 12 Pg. 2028-32 (Dec 2009) ISSN: 1524-4636 [Electronic] United States
• PMID: 19762785 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• HIV Protease Inhibitors
• Insulin
• Lipids
• Pyrazines
• Receptors, LDL
• Glucose
• acipimox
• Ritonavir

Topics

• Adipose Tissue (drug effects, metabolism, pathology)
• Animals
• Antiretroviral Therapy, Highly Active (adverse effects)
• Atherosclerosis (chemically induced, metabolism, prevention & control)
• Glucose (metabolism)
• HIV Protease Inhibitors (administration & dosage, toxicity)
• Humans
• Insulin (pharmacology)
• Lipids (blood)
• Lipolysis (drug effects)
• Mice
• Mice, Knockout
• Models, Biological
• Pyrazines (administration & dosage, pharmacology)
• Receptors, LDL (deficiency, genetics)
• Ritonavir (administration & dosage, toxicity)