Metabolic complications associated with HIV infection and treatment frequently present as a relative lack of peripheral adipose tissue associated with dyslipidemia and insulin resistance. In this review we explain the connection between abnormalities of intermediary metabolism, observed either in vitro or in vivo, and this group of metabolic effects. We review molecular mechanisms by which the HIV protease inhibitor (PI) class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage. We then propose that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on intermediary metabolism. The physiologic outcome is such that total adipocyte storage capacity is decreased, and the remaining adipocytes resist further fat storage. The excess circulating and dietary lipid metabolites, normally “absorbed” by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue, where they impair insulin action. This process leads to a pathologic cycle of lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome.
Arranz Caso, J.A., Lopez, J.C., Santos, I., Estrada, V., Castilla, V., Sanz, J., Molina, J.P., Fernandez Guerrero, M., and Gorgolas, M. ( 2005). A randomized controlled trial investigating the efficacy and safety of switching from a protease inhibitor to nevirapine in patients with undetectable viral load. HIV Med6, 353-59.
2.
Bacchetti, P., Gripshover, B., Grunfeld, C., Heymsfield, S., McCreath, H., Osmond, D., Saag, M., Scherzer, R., Shlipak, M., and Tien, P. ( 2005). Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr40, 121-31.
3.
Barbaro, G. ( 2007). Visceral fat as target of highly active antiretroviral therapy-associated metabolic syndrome. Curr Pharm Des13, 2208-13.
4.
Behrens, G., Dejam, A., Schmidt, H., Balks, H.J., Brabant, G., Korner, T., Stoll, M., and Schmidt, R.E. ( 1999). Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors . AIDS13, F63-70.
5.
Berg, A.H., Combs, T.P., Du, X., Brownlee, M., and Scherer, P.E. ( 2001). The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med7, 947-53.
6.
Brinkman, K., Smeitink, J.A., Romijn, J.A., and Reiss, P. ( 1999). Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet354, 1112-15.
7.
Brown, T.T., Cole, S.R., Li, X., Kingsley, L.A., Palella, F.J., Riddler, S.A., Visscher, B.R., Margolick, J.B., and Dobs, A.S. ( 2005). Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med165, 1179-84.
8.
Buffet, M., Schwarzinger, M., Amellal, B., Gourlain, K., Bui, P., Prevot, M., Deleuze, J., Morini, J.P., Gorin, I., Calvez, V., and Dupin, N. ( 2005). Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy. J Clin Virol33, 60-64.
9.
Cammalleri, C., and Germinario, R.J. (2003). The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling. J Lipid Res44, 103-8.
10.
Caron, M., Auclair, M., Vigouroux, C., Glorian, M., Forest, C., and Capeau, J. ( 2001). The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes50, 1378-88.
11.
Caron, M., Auclair, M., Sterlingot, H., Kornprobst, M., and Capeau, J. ( 2003). Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation . AIDS17, 2437-44.
12.
Caron, M., Auclair, M., Lagathu, C., Lombes, A., Walker, U.A., Kornprobst, M., and Capeau, J. ( 2004). The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS18, 2127-36.
13.
Carr, A., Samaras, K., Burton, S., Law, M., Freund, J., Chisholm, D.J., and Cooper, D.A. ( 1998). A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS12, F51-58.
14.
Charo, I.F., and Taubman, M.B. ( 2004). Chemokines in the pathogenesis of vascular disease . Circ Res95, 858-66.
15.
Coffinier, C., Hudon, S.E., Farber, E.A., Chang, S.Y., Hrycyna, C.A., Young, S.G., and Fong, L.G. ( 2007). HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells. Proc Natl Acad Sci U S A104, 13432-37.
16.
De Barros, S., Zakaroff-Girard, A., Lafontan, M., Galitzky, J., and Bourlier, V. ( 2007). Inhibition of human preadipocyte proteasomal activity by HIV protease inhibitors or specific inhibitor lactacystin leads to a defect in adipogenesis, which involves matrix metalloproteinase-9. J Pharmacol Exp Ther320, 291-99.
17.
DiGirolamo, M., Newby, F.D., and Lovejoy, J. ( 1992). Lactate production in adipose tissue: a regulated function with extra-adipose implications. FASEB J6, 2405-12.
18.
Dube, M.P. ( 2006). HIV-associated lipoatrophy: what are the kinder, gentler agents?Clin Infect Dis42, 281-82.
Dube, M.P., Stein, J.H., Aberg, J.A., Fichtenbaum, C.J., Gerber, J.G., Tashima, K.T., Henry, W.K., Currier, J.S., Sprecher, D., and Glesby, M.J. ( 2003). Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis37, 613-27.
21.
Dube, M.P., Parker, R.A., Tebas, P., Grinspoon, S.K., Zackin, R.A., Robbins, G.K., Roubenoff, R., Shafer, R.W., Wininger, D.A., Meyer, W.A., 3rd, Snyder, S.W., and Mulligan, K. ( 2005). Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS19, 1807-18.
22.
Dubois, M., Kerr-Conte, J., Gmyr, V., Bouckenooghe, T., Muharram, G., D’Herbomez, M., Martin-Ponthieu, A., Vantyghem, M.C., Vandewalle, B., and Pattou, F. ( 2004). Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration. Diabetologia47, 463-69.
23.
Dufer, M., Neye, Y., Krippeit-Drews, P., and Drews, G. ( 2004). Direct interference of HIV protease inhibitors with pancreatic beta-cell function. Naunyn Schmiedebergs Arch Pharmacol369, 583-90.
24.
Estrada, V., Martinez-Larrad, M.T., Gonzalez-Sanchez, J.L., de Villar, N.G., Zabena, C., Fernandez, C., and Serrano-Rios, M. (2006). Lipodystrophy and metabolic syndrome in HIV-infected patients treated with antiretroviral therapy. Metabolism55, 940-45.
25.
Falasca, K., Ucciferri, C., Manzoli, L., Mancino, P., Pizzigallo, E., Conti, P., and Vecchiet, J. ( 2007). Metabolic syndrome and cardiovascular risk in HIV-infected patients with lipodystrophy. Intl J Immunopathol Pharmacol20, 519-27.
26.
Feingold, K.R., Krauss, R.M., Pang, M., Doerrler, W., Jensen, P., and Grunfeld, C. ( 1993). The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab76, 1423-27.
27.
Flint, O.P. ( 1994). In vitro studies of the toxicity of nucleoside analogues used in the treatment of HIV infection. Toxicol In Vitro8, 677-83.
28.
Flint, O.P., Lubinski, L.J., Parker, R.A., and Noor, M. ( 2005). Comparative effects of atazanavir versus other HIV protease inhibitors on glucose and amino acid stimulated insulin secretion . Antivir Ther10, L32.
29.
Friis-Moller, N., Weber, R., Reiss, P., Thiebaut, R., Kirk, O., d’Arminio Monforte, A., Pradier, C., Morfeldt, L., Mateu, S., Law, M., El-Sadr, W., De Wit, S., Sabin, C.A., Phillips, A.N., and Lundgren, J.D. ( 2003). Cardiovascular disease risk factors in HIV patients-association with antiretroviral therapy. Results from the DAD study. AIDS17, 1179-93.
30.
Friis-Moller, N., Reiss, P., Sabin, C.A., Weber, R., Monforte, A., El-Sadr, W., Thiebaut, R., De Wit, S., Kirk, O., Fontas, E., Law, M.G., Phillips, A., and Lundgren, J.D. ( 2007). Class of antiretroviral drugs and the risk of myocardial infarction. New Engl J Med356, 1723-35.
31.
Grinspoon, S.K. ( 2005). Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus. Am J Med118 (Suppl 2), 23S-28S.
32.
Grundy, S.M., Brewer, H.B., Jr., Cleeman, J.I., Smith, S.C., Jr., and Lenfant, C. ( 2004). Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation109, 433-38.
33.
Grunfeld, C., and Kotler, D.P. ( 1992). Wasting in the acquired immunodeficiency syndrome . Semin Liver Dis12, 175-87.
34.
Grunfeld, C., Kotler, D.P., Shigenaga, J.K., Doerrler, W., Tierney, A., Wang, J., Pierson, R.N., Jr., and Feingold, K.R. ( 1991). Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med90, 154-62.
35.
Grunfeld, C., and Tien, P. ( 2003). Difficulties in understanding the metabolic complications of acquired immune deficiency syndrome. Clin Infect Dis37 (Suppl 2), S43-46.
36.
Hadigan, C., Kamin, D., Liebau, J., Mazza, S., Barrow, S., Torriani, M., Rubin, R., Weise, S., Fischman, A., and Grinspoon, S. ( 2006). Depot-specific regulation of glucose uptake and insulin sensitivity in HIV-lipodystrophy. Am J Physiol Endocrinol Metab290, E289-98.
37.
Haerter, G., Manfras, B.J., Mueller, M., Kern, P., and Trein, A. ( 2004). Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir. AIDS18, 952-55.
38.
Hamel, F.G., Fawcett, J., Tsui, B.T., Bennett, R.G., and Duckworth, W.C. ( 2006). Effect of nelfinavir on insulin metabolism, proteasome activity and protein degradation in HepG2 cells. Diabetes Obes Metab8, 661-68.
39.
Haugaard, S.B., Andersen, O., Madsbad, S., Frosig, C., Iversen, J., Nielsen, J.O., and Wojtaszewski, J.F. (2005). Skeletal muscle insulin signaling defects downstream of phosphatidylinositol 3-kinase at the level of Akt are associated with impaired nonoxidative glucose disposal in HIV lipodystrophy . Diabetes54, 3474-83.
40.
He, Q., Engelson, E.S., and Kotler, D.P. ( 2005). A comparison of abdominal subcutaneous adipose tissue pattern in obese and lean HIV-infected women. J Nutr135, 53-57.
41.
Heath, K.V., Chan, K.J., Singer, J., O’Shaughnessy, M.V., Montaner, J.S., and Hogg, R.S. ( 2002). Incidence of morphological and lipid abnormalities: gender and treatment differentials after initiation of first antiretroviral therapy . Int J Epidemiol31, 1016-20.
42.
Hertel, J., Struthers, H., Horj, C.B., and Hruz, P.W. ( 2004). A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. J Biol Chem279, 55147-52.
43.
Hirano, Y., Yoshida, M., Shimizu, M., and Sato, R. ( 2001). Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by the ubiquitin-proteasome pathway . J Biol Chem276, 36431-37.
44.
Hommes, M.J., Romijn, J.A., Endert, E., Eeftinck Schattenkerk, J.K., and Sauerwein, H.P. ( 1991a). Basal fuel homoeostasis in symptomatic human immunodeficiency virus infection. Clin Sci ( Lond) 80, 359-65.
45.
Hommes, M.J., Romijn, J.A., Endert, E., Eeftinck Schattenkerk, J.K., and Sauerwein, H.P. ( 1991b). Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men. Metabolism40, 651-56.
46.
Horton, J.D., Goldstein, J.L., and Brown, M.S. ( 2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest109, 1125-31.
47.
Hruz, P.W., Murata, H., Qiu, H., and Mueckler, M. ( 2002). Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes51, 937-42.
48.
Jacobson, D.L., Knox, T., Spiegelman, D., Skinner, S., Gorbach, S., and Wanke, C. ( 2005). Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-infected men and women . Clin Infect Dis40, 1837-45.
49.
Jemsek, J.G., Arathoon, E., Arlotti, M., Perez, C., Sosa, N., Pokrovskiy, V., Thiry, A., Soccodato, M., Noor, M.A., and Giordano, M. ( 2006). Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients. Clin Infect Dis42, 273-80.
50.
Kakuda, T.N., Brundage, R.C., Anderson, P.L., and Fletcher, C.V. ( 1999). Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. AIDS13, 2311-12.
51.
Kaplan, R.C., Kingsley, L.A., Sharrett, A.R., Li, X., Lazar, J., Tien, P.C., Mack, W.J., Cohen, M.H., Jacobson, L., and Gange, S.J. ( 2007). Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis45, 1074-81.
52.
Katzmarzyk, P.T., Perusse, L., and Bouchard, C. ( 1999). Genetics of abdominal visceral fat levels. Am J Human Biol11, 225-35.
53.
Kaufman, R.J., Scheuner, D., Schroder, M., Shen, X., Lee, K., Liu, C.Y., and Arnold, S.M. ( 2002). The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol3, 411-21.
Large, V., Peroni, O., Letexier, D., Ray, H., and Beylot, M. ( 2004). Metabolism of lipids in human white adipocyte . Diabetes Metab30, 294-309.
56.
Lee, H., Hanes, J., and Johnson, K.A. ( 2003). Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry42, 14711-19.
57.
Lee, G.A., Mafong, D.D., Lo, J.C., Schwarz, J.M., Aweeka, F.T., Mulligan, M., Schambelan, M., and Grunfeld, C. ( 2004). Ritonavir acutely induces insulin resistance in healthy normal volunteers. Antiviral Therapy9, L6.
58.
Lee, G.A., Rao, M.N., and Grunfeld, C. ( 2004). The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr Infect Dis Rep6, 471-82.
59.
Lee, G.A., Seneviratne, T., Noor, M.A., Lo, J.C., Schwarz, J.M., Aweeka, F.T., Mulligan, K., Schambelan, M., and Grunfeld, C. ( 2004). The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS18, 641-49.
60.
Lee, G.A., Rao, M.N., and Grunfeld, C. ( 2005). The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr HIV/AIDS Rep2, 39-50.
61.
Lee, G.A., Rao, M.N., Schwarz, J.M., Aweeka, F.T., and Grunfeld, C. ( 2005). A single dose of amprenavir does not induce insulin resistance in healthy normal volunteers. Antivir Ther10, L11.
62.
Lee, G.A., Lo, J.C., Aweeka, F., Schwarz, J.M., Mulligan, K., Schambelan, M., and Grunfeld, C. ( 2006). Single-dose lopinavir-ritonavir acutely inhibits insulin-mediated glucose disposal in healthy volunteers. Clin Infect Dis43, 658-60.
63.
Liang, J.S., Distler, O., Cooper, D.A., Jamil, H., Deckelbaum, R.J., Ginsberg, H.N., and Sturley, S.L. ( 2001). HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med7, 1327-31.
64.
Lum, P.Y., He, Y.D., Slatter, J.G., Waring, J.F., Zelinsky, N., Cavet, G., Dai, X., Fong, O., Gum, R., Jin, L., Adamson, G.E., Roberts, C.J., Olsen, D.B., Hazuda, D.J., and Ulrich, R.G. ( 2007). Gene expression profiling of rat liver reveals a mechanistic basis for ritonavir-induced hyperlipidemia. Genomics90, 464-73.
65.
Lund, K.C., Peterson, L.L., and Wallace, K.B. ( 2007). Absence of a universal mechanism of mitochondrial toxicity by nucleoside analogs. Antimicrob Agents Chemother51, 2531-39.
66.
Lund, K.C., and Wallace, K.B. ( 2004). Direct effects of nucleoside reverse transcriptase inhibitors on rat cardiac mitochondrial bioenergetics. Mitochondrion4, 193-202.
67.
Mallal, S.A., John, M., Moore, C.B., James, I.R., and McKinnon, E.J. ( 2000). Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS14, 1309-16.
68.
Mallon, P.W., Miller, J., Cooper, D.A., and Carr, A. ( 2003). Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS17, 971-79.
69.
Mallon, P.W. ( 2007). Pathogenesis of lipodystrophy and lipid abnormalities in patients taking antiretroviral therapy. AIDS Rev9, 3-15.
70.
McComsey, G.A., Ward, D.J., Hessenthaler, S.M., Sension, M.G., Shalit, P., Lonergan, J.T., Fisher, R.L., Williams, V.C., and Hernandez, J.E. ( 2004). Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study . Clin Infect Dis38, 263-70.
71.
Miller, J., Carr, A., Emery, S., Law, M., Mallal, S., Baker, D., Smith, D., Kaldor, J., and Cooper, D.A. ( 2003). HIV lipodystrophy: prevalence, severity and correlates of risk in Australia. HIV Med4, 293-301.
72.
Mulligan, K., Tai, V.W., and Schambelan, M. ( 1997). Cross-sectional and longitudinal evaluation of body composition in men with HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol15, 43-48.
73.
Mulligan, K., Grunfeld, C., Tai, V.W., Algren, H., Pang, M., Chernoff, D.N., Lo, J.C., and Schambelan, M. ( 2000). Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr23, 35-43.
74.
Mulligan, K., Parker, R.A., Komarow, L., Grinspoon, S.K., Tebas, P., Robbins, G.K., Roubenoff, R., and Dube, M.P. ( 2006). Mixed patterns of changes in central and peripheral fat following initiation of antiretroviral therapy in a randomized trial. J Acquir Immune Defic Syndr41, 590-97.
75.
Murata, H., Hruz, P.W., and Mueckler, M. ( 2000). The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem275, 20251-54.
76.
Murata, H., Hruz, P.W., and Mueckler, M. ( 2002). Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS16, 859-63.
77.
Nawaz, Z., and O’Malley, B.W. (2004). Urban renewal in the nucleus: is protein turnover by proteasomes absolutely required for nuclear receptor-regulated transcription?Mol Endocrinol18, 493-99.
78.
Nolte, L.A., Yarasheski, K.E., Kawanaka, K., Fisher, J., Le, N., and Holloszy, J.O. ( 2001). The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle. Diabetes50, 1397-401.
79.
Noor, M., Dezii, C., C., M., Wirtz, V., Maa, J., Bessen, L., and Hodder, S. ( 2004). Baseline triglyceride levels predict development of lipoatrophy in patients treated with stavudine extended-release/prolonged-release capsules or stavudine immediate-release. In 11th Conferece on Retroviruses and Opportunistic Infections, San Francisco .
80.
Noor, M.A., Flint, O.P., Maa, J.F., and Parker, R.A. ( 2006). Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically. AIDS20, 1813-21.
81.
Noor, M.A., Lo, J.C., Mulligan, K., Schwarz, J.M., Halvorsen, R.A., Schambelan, M., and Grunfeld, C. ( 2001). Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS15, F11-18.
82.
Noor, M.A., Parker, R.A., O’Mara, E., Grasela, D.M., Currie, A., Hodder, S.L., Fiedorek, F.T., and Haas, D.W. ( 2004). The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults . AIDS18, 2137-44.
83.
Noor, M.A., Seneviratne, T., Aweeka, F.T., Lo, J.C., Schwarz, J.M., Mulligan, K., Schambelan, M., and Grunfeld, C. ( 2002). Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS16, F1-8.
84.
Pajonk, F., Himmelsbach, J., Riess, K., Sommer, A., and McBride, W.H. ( 2002). The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res62, 5230-35.
85.
Parker, R.A., Flint, O.P., Mulvey, R., Elosua, C., Wang, F., Fenderson, W., Wang, S., Yang, W.P., and Noor, M.A. ( 2005). Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. Mol Pharmacol67, 1909-19.
86.
Pinti, M., Salomoni, P., and Cossarizza, A. ( 2006). Anti-HIV drugs and the mitochondria. Biochim Biophys Acta1757, 700-7.
87.
Prot, M., Heripret, L., Cardot-Leccia, N., Perrin, C., Aouadi, M., Lavrut, T., Garraffo, R., Dellamonica, P., Durant, J., Le Marchand-Brustel, Y., and Binetruy, B. ( 2006). Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice. Antimicrob Agents Chemother50, 3998-4004.
88.
Purnell, J.Q., Zambon, A., Knopp, R.H., Pizzuti, D.J., Achari, R., Leonard, J.M., Locke, C., and Brunzell, J.D. ( 2000). Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS14, 51-57.
89.
Reeds, D.N., Cade, W.T., Patterson, B.W., Powderly, W.G., Klein, S., and Yarasheski, K.E. (2006). Whole-body proteolysis rate is elevated in HIV-associated insulin resistance. Diabetes55, 2849-55.
90.
Reeds, D.N., Yarasheski, K.E., Fontana, L., Cade, W.T., Laciny, E., DeMoss, A., Patterson, B.W., Powderly, W.G., and Klein, S. ( 2006). Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia. Am J Physiol Endocrinol Metab290, E47-E53.
91.
Riddle, T.M., Kuhel, D.G., Woollett, L.A., Fichtenbaum, C.J., and Hui, D.Y. ( 2001). HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem276, 37514-19.
92.
Riddler, S.A., Smit, E., Cole, S.R., Li, R., Chmiel, J.S., Dobs, A., Palella, F., Visscher, B., Evans, R., and Kingsley, L.A. ( 2003). Impact of HIV infection and HAART on serum lipids in men. JAMA289, 2978-82.
93.
Roche, R., Poizot-Martin, I., Yazidi, C.M., Compe, E., Gastaut, J.A., Torresani, J., and Planells, R. ( 2002). Effects of antiretroviral drug combinations on the differentiation of adipocytes. AIDS16, 13-20.
94.
Ron, D., and Walter, P. ( 2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol8, 519-29.
95.
Rudich, A., Ben-Romano, R., Etzion, S., and Bashan, N. ( 2005). Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. Acta Physiol Scand183, 75-88.
96.
Safrin, S., and Grunfeld, C. ( 1999). Fat distribution and metabolic changes in patients with HIV infection. AIDS13, 2493-505.
97.
Samaras, K., Wand, H., Law, M., Emery, S., Cooper, D., and Carr, A. ( 2007). Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia. Diabetes Care30, 113-19.
98.
Schmidtke, G., Holzhutter, H.G., Bogyo, M., Kairies, N., Groll, M., de Giuli, R., Emch, S., and Groettrup, M. ( 1999). How an inhibitor of the HIV-I protease modulates proteasome activity. J Biol Chem274, 35734-40.
99.
Schutt, M., Meier, M., Meyer, M., Klein, J., Aries, S.P., and Klein, H.H. ( 2000). The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells. Diabetologia43, 1145-48.
100.
Sekhar, R.V., Jahoor, F., Pownall, H.J., Rehman, K., Gaubatz, J., Iyer, D., and Balasubramanyam, A. (2005). Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome. Am J Clin Nutr81, 1405-10.
101.
Shahmanesh, M., Das, S., Stolinski, M., Shojaee-Moradie, F., Jackson, N.C., Jefferson, W., Cramb, R., Nightingale, P., and Umpleby, A.M. ( 2005). Antiretroviral treatment reduces very-low-density lipoprotein and intermediate-density lipoprotein apolipoprotein B fractional catabolic rate in human immunodeficiency virus-infected patients with mild dyslipidemia . J Clin Endocrinol Metab90, 755-60.
102.
Shikuma, C.M., Day, L.J., and Gerschenson, M. ( 2005). Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. Curr Drug Targets Infect Disord5, 255-62.
103.
Shlay, J.C., Visnegarwala, F., Bartsch, G., Wang, J., Peng, G., El-Sadr, W.M., Gibert, C., Kotler, D., Grunfeld, C., and Raghavan, S. ( 2005). Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine . J Acquir Immune Defic Syndr38, 147-55.
104.
Staiger, H., Tschritter, O., Machann, J., Thamer, C., Fritsche, A., Maerker, E., Schick, F., Haring, H.U., and Stumvoll, M. ( 2003). Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes Res11, 368-72.
105.
Straczkowski, M., Kowalska, I., Nikolajuk, A., Dzienis-Straczkowska, S., Kinalska, I., Baranowski, M., Zendzian-Piotrowska, M., Brzezinska, Z., and Gorski, J. ( 2004). Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes53, 1215-21.
106.
Summers, S.A., and Nelson, D.H. ( 2005). A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing’s syndrome . Diabetes54, 591-602.
107.
Travers, K.J., Patil, C.K., Wodicka, L., Lockhart, D.J., Weissman, J.S., and Walter, P. ( 2000). Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation . Cell101, 249-58.
108.
Unger, R.H. ( 2003). Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology144, 5159-65.
109.
van der Valk, M., Bisschop, P.H., Romijn, J.A., Ackermans, M.T., Lange, J.M., Endert, E., Reiss, P., and Sauerwein, H.P. ( 2001). Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS15, 2093-100.
110.
Vigouroux, C., Maachi, M., Nguyen, T.H., Coussieu, C., Gharakhanian, S., Funahashi, T., Matsuzawa, Y., Shimomura, I., Rozenbaum, W., Capeau, J., and Bastard, J.P. ( 2003). Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy. AIDS17, 1503-11.
111.
Villarroya, F., Domingo, P., and Giralt, M. ( 2005). Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. Trends Pharmacol Sci26, 88-93.
112.
Walli, R., Herfort, O., Michl, G.M., Demant, T., Jager, H., Dieterle, C., Bogner, J.R., Landgraf, R., and Goebel, F.D. ( 1998). Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients . AIDS12, F167-73.
113.
Wand, H., Law, M.G., Emery, S., Cooper, D.A., and Carr, A. ( 2005). Increase in limb fat after nucleoside analogue cessation is not associated with decreased visceral fat and has different risk factors . Antivir Ther10, L5.
114.
Wand, H., Calmy, A., Carey, D.L., Samaras, K., Carr, A., Law, M.G., Cooper, D.A., and Emery, S. ( 2007). Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection . AIDS21, 2445-53.
115.
Waters, L., and Nelson, M. ( 2007). Long-term complications of antiretroviral therapy: lipoatrophy . Intl J Clin Pract61, 999-1014.
116.
Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R.E., and Tataranni, P.A. ( 2001). Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab86, 1930-35.
117.
Williams, K., Rao, Y.P., Natarajan, R., Pandak, W.M., and Hylemon, P.B. ( 2004). Indinavir alters sterol and fatty acid homeostatic mechanisms in primary rat hepatocytes by increasing levels of activated sterol regulatory element-binding proteins and decreasing cholesterol 7alpha-hydroxylase mRNA levels. Biochem Pharmacol67, 255-67.
118.
Woerle, H.J., Mariuz, P.R., Meyer, C., Reichman, R.C., Popa, E.M., Dostou, J.M., Welle, S.L., and Gerich, J.E. ( 2003). Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes52, 918-25.
119.
Wohl, D.A., McComsey, G., Tebas, P., Brown, T.T., Glesby, M.J., Reeds, D., Shikuma, C., Mulligan, K., Dube, M., Wininger, D., Huang, J., Revuelta, M., Currier, J., Swindells, S., Fichtenbaum, C., Basar, M., Tungsiripat, M., Meyer, W., Weihe, J., and Wanke, C. ( 2006). Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis43, 645-53.
120.
Xu, A., Yin, S., Wong, L., Chan, K.W., and Lam, K.S. ( 2004). Adiponectin ameliorates dyslipidemia induced by the human immunodeficiency virus protease inhibitor ritonavir in mice. Endocrinology145, 487-94.
121.
Xu, C., Bailly-Maitre, B., and Reed, J.C. ( 2005). Endoplasmic reticulum stress: cell life and death decisions . J Clin Invest115, 2656-64.
122.
Yan, Q., and Hruz, P.W. ( 2005). Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal. J Acquir Immune Defic Syndr40, 398-403.
123.
Zhang, K., and Kaufman, R.J. ( 2004). Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem279, 25935-38.
124.
Zhou, J.Q., Li, W.P., Xiang, Z., and Schutt, M. ( 2006). Effects of various HIV protease inhibitors on function of rat insulinoma cells [in Chinese]. Zhejiang da xue xue bao. Yi xue ban (Journal of Zhejiang University)35, 251-54.
