Adiponectin ameliorates dyslipidemia induced by the human immunodeficiency virus protease inhibitor ritonavir in mice.
Although the clinical application of HIV protease inhibitors (PIs) has markedly reduced HIV-related morbidity and mortality, it is now recognized that PI-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 the adiponectin gene and secretion of this protein from 3T3-L1 adipocytes are significantly decreased after treatment with several PIs (indinavir, nelfinavir, and ritonavir), with ritonavir having the greatest effect. Intragastric 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. In contrast, 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.
Xu
Aimin
A
Department of Medicine, The University of Hong Kong, L8-33A, New Laboratory Block, 21 Sassoon Road, Hong Kong, China. amxu@hkucc.hku.hk
Yin
Shinan
S
Wong
Laiching
L
Chan
Kok Weng
KW
Lam
Karen S L
KS
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D020249:Hormone Replacement Therapy; D006949:Hyperlipidemias / Q000139:chemically induced*; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D019438:Ritonavir / Q000009:adverse effects* / Q000494:pharmacology; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood
D052242:Adiponectin; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D017320:HIV Protease Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; D014280:Triglycerides; D002784:Cholesterol; D019438:Ritonavir