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Submitted on September 2, 2003
Accepted on October 21, 2003
1 Department of Medicine, The University of Hong Kong, Hong Kong, China.
* To whom correspondence should be addressed. E-mail: amxu{at}hkucc.hku.hk.
Although the clinical application of HIV protease inhibitors (PIs) has markedly reduced HIV-related morbidity and mortality, it is now recognized that PIs-based therapy often causes serious metabolic disorders, including hyperlipidemia and premature atherosclerosis. The etiology of these adverse effects remains obscure. Here, we demonstrate that deficiency of the fat-derived hormone adiponectin might play a role. The steady-state mRNA levels of adiponectin gene and secretion of this protein from 3T3-L1 adipocytes are significantly decreased following treatment with several PIs (indinavir, nelfinavir and ritonavir), with ritonavir having the greatest effect. Intra-gastric administration of ritonavir into mice decreases plasma concentrations of adiponectin, and concurrently increases the plasma levels of triglyceride, free fatty acids and cholesterol. Adiponectin replacement therapy markedly ameliorates ritonavir-induced elevations of triglyceride and free fatty acids. These beneficial effects of adiponectin are partly due to its ability to decrease ritonavir-induced synthesis of fatty acids and triglyceride, and to increase fatty acid combustion in the liver tissue. One the other hand, adiponectin has little effect on ritonavir-induced hypercholesterolemia and hepatic cholesterol synthesis. These results suggest that hypoadiponectinemia is partly responsible for the metabolic disorders induced by HIV PIs, and adiponectin or its agonists might be useful for the treatment of these disorders.
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