The Protease Inhibitors Ritonavir and Saquinavir Influence Lipid Metabolism: A Pig Model for the Rapid Evaluation of New Drugs

Carr A. , Emery S. , Law M. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet 2003; 361: 726–735.

DAD Study Group, Friis-Møller N. , Reiss P. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356: 1723–1735.

D:A:D Study Group, Sabin C.A. , Worm S.W. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371: 1417–1426.

Parker R.A. , Flint O.P. , Mulvey R. Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. Mol Pharmacol 2005; 67: 1909–1919.

Squillace N. , Zona S. , Stentarelli C. Detectable HIV viral load is associated with metabolic syndrome. J Acquir Immune Defic Syndr 2009; 52: 459–464.

Carr A. , Ritzhaupt A. , Zhang W. Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults. AIDS 2008; 22: 2313–2321.

Tebas P. Insulin resistance and diabetes mellitus associated with antiretroviral use in HIV-infected patients: pathogenesis, prevention, and treatment options. J Acquir Immune Defic Syndr 2008; 49 Suppl 2: S86–S92.

Flint O.P. , Noor M.A. , Hruz P.W. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol Pathol 2009; 37: 65–77.

Reeds D.N. , Mittendorfer B. , Patterson B.W. , Powderly W.G. , Yarasheski K.E. , Klein S. Alterations in lipid kinetics in men with HIV-dyslipidemia. Am J Physiol Endocrinol Metab 2003; 285: E490–E497.

Ghibelli L. , Mengoni F. , Lichtner M. Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain. Biochem Pharmacol 2003; 66: 1505–1512.

Carr A. , Samaras K. , Chisholm D.J. , Cooper D.A. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–1883.

Walker U.A. , Bickel M. , Lütke Volksbeck S.I. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002; 29: 117–121.

Ranade K. , Geese W.J. , Noor M. Genetic analysis implicates resistin in HIV lipodystrophy. AIDS 2008; 22: 1561–1568.

Adeyemi O. , Rezai K. , Bahk M. , Badri S. , Thomas-Gossain N. Metabolic syndrome in older HIV-infected patients: data from the CORE50 cohort. AIDS Patient Care STDS 2008; 22: 941–945.

Mallon P. W. . Pathogenesis of lipodystrophy and lipid abnormalities in patients taking antiretroviral therapy. AIDS Rev 2007; 9: 3–15.

Ntawubizi M. , Raes K. , Buys N. , De Smet S. Relationships between indices for desaturase and elongase activity involved in the intramuscular long chain polyunsaturated fatty acid metabolism in pigs. Commun Agric Appl Biol Sci 2007; 72: 29–33.

Hsu A. , Granneman G.R. , Witt G. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997; 41: 898–905.

Justesen U.S. Protease inhibitor plasma concentrations in HIV antiretroviral therapy. Dan Med Bull 2008; 55: 165–184.

Justesen U.S. , Fox Z. , Pedersen C. Pharmacokinetics of two randomized trials evaluating the safety and efficacy of indinavir, saquinavir and lopinavir in combination with low-dose ritonavir: the MaxCmin1 and 2 trials. Basic Clin Pharmacol Toxicol 2007; 101: 339–344.

Kotler D.P. HIV and antiretroviral therapy: lipid abnormalities and associated cardiovascular risk in HIV-infected patients. J Acquir Immune Defic Syndr 2008; 49 Suppl 2: S79–S85.

Purnell J.Q. , Zambon A. , Knopp R.H. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 2000; 14: 51–57.

Martínez E. , García-Viejo M.A. , Blanco J.L. Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. Clin Infect Dis 2000; 31: 1266–1273.

Bastard J.P. , Caron M. , Vidal H. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002; 359: 1026–1031.

Jones S.P. , Qazi N. , Morelese J. Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens. J Acquir Immune Defic Syndr 2005; 40: 565–572.

Lagathu C. , Kim M. , Maachi M. HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo. Biochimie 2005; 87: 65–71.

Mallewa J.E. , Wilkins E. , Vilar J. HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother 2008; 62: 648–660.

Domingo P. , Matias-Guiu X. , Pujol R.M. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 1999; 13: 2261–2267.

Ranganathan S. , Kern P.A. The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocyte. J Endocrinol 2002; 172: 155–162.

Noor M.A. , Seneviratne T. , Aweeka F.T. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2002; 16: 1–8.

Shimano H. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 2001; 40: 439–452.

Qin Y. , Dalen K.T. , Gustafsson J.A. , Nebb H.I. Regulation of hepatic fatty acid elongase 5 by LXRalpha-SREBP-1c. Biochim Biophys Acta 2009; 1791: 140–147.

Wang Y. , Botolin D. , Xu J. Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J Lipid Res 2006; 47: 2028–2041.

Rasheed S. , Yan J.S. , Lau A. , Chan A.S. HIV replication enhances production of free fatty acids, low density lipoproteins and many key proteins involved in lipid metabolism: a proteomics study. PLoS ONE 2008; 3: e3003.

Murakami K. , Sasaki S. , Takahashi Y. Lower estimates of delta-5 desaturase and elongase activity are related to adverse profiles for several metabolic risk factors in young Japanese women. Nutr Res 2008; 28: 816–824.

Matsuzaka T. , Shimano H. , Yahagi N. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat Med 2007; 13: 1193–1202.

Tanaka T. , Shen J. , Abecasis G.R. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet 2009; 5: e1000338.

Hara K. , Yamauchi T. , Kadowaki T. Adiponectin: an adipokine linking adipocytes and type 2 diabetes in humans. Curr Diab Rep 2005; 5: 136–140.

Lindegaard B. , Keller P. , Bruunsgaard H. , Gerstoft J. , Pedersen B.K. Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients. Clin Exp Immunol 2004; 135: 273–279.

Liang J.S. , Distler O. , Cooper D.A. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 2001; 7: 1327–1331.

Koutkia P. , Canavan B. , Breu J. , Grinspoon S. Effects of growth hormone-releasing hormone on bone turnover in human immunodeficiency virus-infected men with fat accumulation. J Clin Endocrinol Metab 2005; 90: 2154–2160.

Brennan A.M. , Lee J.H. , Tsiodras S. r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. Eur J Endocrinol 2009; 160: 173–176.