CD36 deficiency induced by antiretroviral therapy

Background The molecular basis of lipodystrophy, a syndrome associated with HIV antiretroviral (ARV) therapy, remains unknown. Objectives To examine whether ARV therapy might inhibit the expression of CD36, which is known to play an important role in fatty acid and glucose metabolism, and if this might contribute to the metabolic alterations associated with lipodystrophy. Design The effects of ARV therapy on CD36 levels was examined in vivo in a prospective cohort of individuals treated with ARV therapy and in vitro in assays of human cell lines exposed to ARV drugs. Methods Monocyte CD36 levels were assessed by flow cytometry at baseline and after 7 days of therapy in five healthy volunteers and 10 treatment-naive HIV-1-infected individuals. ARV therapy included protease inhibitors (ritonavir, nelfinavir or lopinavir/ritonavir). In addition, human cell lines (THP-1 and C32) were assessed for CD36 levels pre and post-ritonavir treatment. Results Three of four healthy controls (one withdrew because of adverse effects) and 6 of 10 HIV-1-infected individuals had a 50 to > 90% decrease in monocyte CD36 levels after 7 days of therapy. One of ten HIV-infected subjects had a 30% decrease, and the remaining individuals had no change or an increase in CD36 levels. CD36 levels decreased significantly in human cell lines treated with ritonavir but not in those treated with zidovudine. Conclusions ARV therapy resulted in a marked decrease in CD36 in approximately 70% of our participants. Sustained ARV therapy-induced CD36 deficiency may contribute to insulin resistance and other metabolic complications of lipodystrophy.

[1]  T. Aitman.  CD36, insulin resistance, and coronary heart disease , 2001, The Lancet.

[2]  S. Yamashita,et al.  CD36 deficiency associated with insulin resistance , 2001, The Lancet.

[3]  T. Kurtz,et al.  Transgenic rescue of defective Cd36 ameliorates insulin resistance in spontaneously hypertensive rats , 2001, Nature Genetics.

[4]  J. Connell,et al.  Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat. , 2000, Diabetes.

[5]  M. Jaye,et al.  PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. , 2000, Nature medicine.

[6]  D. Cooper,et al.  Adverse effects of antiretroviral therapy , 2000, The Lancet.

[7]  R. Silverstein,et al.  Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice* , 2000, The Journal of Biological Chemistry.

[8]  K. Sepkowitz,et al.  Coronary artery disease and human immunodeficiency virus infection. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  B. Spiegelman,et al.  Peroxisome proliferator–activated receptor γ ligands and atherosclerosis: ending the heartache , 2000 .

[10]  Andrew C. Li,et al.  Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice , 2000 .

[11]  H. Chiba,et al.  Human CD36 deficiency is associated with elevation in low-density lipoprotein-cholesterol. , 2000, American journal of medical genetics.

[12]  S. Hazen,et al.  Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. , 2000, The Journal of clinical investigation.

[13]  M. Hofker,et al.  Scavenging new insights into atherogenesis. , 2000, The Journal of clinical investigation.

[14]  V. Chatterjee,et al.  HIV protease inhibitors block human preadipocyte differentiation, but not via the PPARgamma/RXR heterodimer. , 2000, The Journal of endocrinology.

[15]  J. Berger,et al.  Inhibition of adipocyte differentiation by HIV protease inhibitors. , 1999, The Journal of clinical endocrinology and metabolism.

[16]  P. Reiss,et al.  Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy , 1999, The Lancet.

[17]  A. Bonen,et al.  Muscle-specific Overexpression of FAT/CD36 Enhances Fatty Acid Oxidation by Contracting Muscle, Reduces Plasma Triglycerides and Fatty Acids, and Increases Plasma Glucose and Insulin* , 1999, The Journal of Biological Chemistry.

[18]  F. Goebel,et al.  Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus , 1999, Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie.

[19]  R. Silverstein,et al.  A Null Mutation in Murine CD36 Reveals an Important Role in Fatty Acid and Lipoprotein Metabolism* , 1999, The Journal of Biological Chemistry.

[20]  D. Cooper,et al.  Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: acohort study , 1999, The Lancet.

[21]  F. Goebel,et al.  Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV‐1‐infected patients , 1998, AIDS.

[22]  D. Cooper,et al.  Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance , 1998, The Lancet.

[23]  M. Compton,et al.  Leptin regulation of peroxisome proliferator-activated receptor-gamma, tumor necrosis factor, and uncoupling protein-2 expression in adipose tissues. , 1998, Biochemical and biophysical research communications.

[24]  David A. Cooper,et al.  A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors , 1998, AIDS.

[25]  K. Henry,et al.  Severe premature coronary artery disease with protease inhibitors , 1998, The Lancet.

[26]  R. Evans,et al.  Oxidized LDL Regulates Macrophage Gene Expression through Ligand Activation of PPARγ , 1998, Cell.

[27]  R. Evans,et al.  PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL , 1998, Cell.

[28]  H. Hein,et al.  Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. , 1998, Circulation.

[29]  H. Brodt,et al.  Changing incidence of AIDS‐defining illnesses in the era of antiretroviral combination therapy , 1997, AIDS.

[30]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[31]  M A Fischl,et al.  A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. , 1997, The New England journal of medicine.

[32]  R. Krauss,et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. , 1996, JAMA.

[33]  R. Graves,et al.  Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor gamma , 1996, Molecular and cellular biology.

[34]  B Wise,et al.  Antiretroviral therapy in adults. , 1996, Journal of the American Academy of Nurse Practitioners.

[35]  S. Yamashita,et al.  Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. , 1995, The Journal of clinical investigation.

[36]  B. Spiegelman,et al.  Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor , 1994, Cell.

[37]  P. Grimaldi,et al.  Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. , 1993, The Journal of biological chemistry.

[38]  D. Altshuler,et al.  The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. , 2001, Nature medicine.

[39]  M. Jaye,et al.  PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway , 2001, Nature Medicine.

[40]  D. Altshuler,et al.  The role of PPAR-γ in macrophage differentiation and cholesterol uptake , 2001, Nature Medicine.

[41]  J. Connell,et al.  Cd 36 and Molecular Mechanisms of Insulin Resistance in the Stroke-Prone Spontaneously Hypertensive Rat , 2000 .

[42]  M A Fischl,et al.  Antiretroviral Therapy in Adults Updated Recommendations of the International AIDS Society–USA Panel , 2000 .

[43]  B. Spiegelman,et al.  Peroxisome proliferator-activated receptor gamma ligands and atherosclerosis: ending the heartache. , 2000, The Journal of clinical investigation.

[44]  Eyton,et al.  A CONTROLLED TRIAL OF TWO NUCLEOSIDE ANALOGUES PLUS INDINAVIR IN PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND CD4 CELL COUNTS OF 200 PER CUBIC MILLIMETER OR LESS , 2000 .

[45]  James Scott,et al.  Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats , 1999, Nature Genetics.

[46]  K. Kawamura,et al.  Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? , 1997, Journal of molecular and cellular cardiology.