HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes.

Treatment of human immunodeficiency virus (HIV)-infected patients with HIV protease inhibitors (PIs) has been associated with serious lipid disturbances. However, the incidence and degree of impaired lipid metabolism observed in the clinic vary considerably between individual HIV PIs. Our previous studies demonstrated that HIV PIs differ in their ability to increase the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs), activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. In the present study, we examined the effects of three HIV PIs, including amprenavir, atazanavir, and ritonavir, on the UPR activation and the expression of key genes involved in lipid metabolism in primary rodent hepatocytes. Both atazanavir and ritonavir activated the UPR, induced apoptosis, and increased nuclear SREBP levels, but amprenavir had no significant effect at the same concentrations. In rat primary hepatocytes, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels were significantly decreased by atazanavir (38%) and ritonavir (56%) but increased by amprenavir (90%); 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase mRNA levels were increased by amprenavir (23%) but not by ritonavir and atazanavir; low-density lipoprotein receptor mRNA was increased by atazanavir (20%) but not by amprenavir and ritonavir. Similar results were obtained in mouse primary hepatocytes. Atazanavir and ritonavir also decreased CYP7A1 protein levels and bile acid biosynthesis, while amprenavir had no significant effect. The current results may help provide a better understanding of the cellular mechanisms of HIV PI-induced dyslipidemia and also provide useful information to help predict clinical adverse effects in the development of new HIV PIs.

[1]  P. Hylemon,et al.  Cellular mechanisms of lipodystrophy induction by HIV protease inhibitors , 2006 .

[2]  P. Sax.  Strategies for management and treatment of dyslipidemia in HIV/AIDS , 2006, AIDS care.

[3]  Neil Kaplowitz,et al.  Liver biology and pathobiology , 2006, Hepatology.

[4]  P. Reiss,et al.  Ritonavir Impairs Lipoprotein Lipase–Mediated Lipolysis and Decreases Uptake of Fatty Acids in Adipose Tissue , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[5]  C. Cohen.  Ritonavir-boosted protease inhibitors, Part 2: cardiac implications of lipid alterations. , 2005, The AIDS reader.

[6]  Q. Yao,et al.  HIV protease inhibitor ritonavir increases endothelial monolayer permeability. , 2005, Biochemical and biophysical research communications.

[7]  P. Hylemon,et al.  HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease , 2005, Molecular Pharmacology.

[8]  B. Clotet,et al.  Review of atazanavir: a novel HIV protease inhibitor , 2005, Expert opinion on pharmacotherapy.

[9]  R. Parker,et al.  Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors , 2005, Molecular Pharmacology.

[10]  M. Mostert,et al.  The HIV Protease Inhibitors Nelfinavir and Saquinavir, but Not a Variety of HIV Reverse Transcriptase Inhibitors, Adversely Affect Human Proteasome Function , 2005, Antiviral therapy.

[11]  Madhu N. Rao,et al.  The effects of HIV protease inhibitors on carbohydrate and lipid metabolism , 2004, Current infectious disease reports.

[12]  F. Foufelle,et al.  SREBP transcription factors: master regulators of lipid homeostasis. , 2004, Biochimie.

[13]  Joon-No Lee,et al.  Proteolytic Activation of Sterol Regulatory Element-binding Protein Induced by Cellular Stress through Depletion of Insig-1* , 2004, Journal of Biological Chemistry.

[14]  Adriano Lazzarin,et al.  Atazanavir—A Once-daily HIV Protease Inhibitor That Does Not Cause Dyslipidemia in Newly Treated Patients: Results from Two Randomized Clinical Trials , 2004, Journal of the International Association of Physicians in AIDS Care.

[15]  R. Kaufman,et al.  Signaling the Unfolded Protein Response from the Endoplasmic Reticulum* , 2004, Journal of Biological Chemistry.

[16]  D. Havlir,et al.  Atazanavir: new option for treatment of HIV infection. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  J. Gatell,et al.  Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  M. Sulkowski.  Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  P. Hylemon,et al.  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. , 2004, Biochemical pharmacology.

[20]  Michael Giordano,et al.  Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results , 2003, AIDS.

[21]  G. Shore,et al.  Regulation of apoptosis by endoplasmic reticulum pathways , 2003, Oncogene.

[22]  P. Clevenbergh,et al.  Impact of Various Antiretroviral Drugs and Their Plasma Concentrations on Plasma Lipids in Heavily Pretreated HIV-Infected Patients , 2003, HIV clinical trials.

[23]  R. B. Rawson.  The SREBP pathway — insights from insigs and insects , 2003, Nature Reviews Molecular Cell Biology.

[24]  F. Pulido,et al.  Lipid changes in HIV-infected patients who started rescue therapy with an amprenavir/ritonavir-based highly active antiretroviral therapy. , 2002, AIDS.

[25]  Frank Pajonk,et al.  The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. , 2002, Cancer research.

[26]  Joseph L Goldstein,et al.  SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. , 2002, The Journal of clinical investigation.

[27]  C. Fichtenbaum,et al.  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* , 2001, The Journal of Biological Chemistry.

[28]  Minoru Yoshida,et al.  Direct Demonstration of Rapid Degradation of Nuclear Sterol Regulatory Element-binding Proteins by the Ubiquitin-Proteasome Pathway* , 2001, The Journal of Biological Chemistry.

[29]  L. Ellerby,et al.  Coupling Endoplasmic Reticulum Stress to the Cell Death Program , 2001, The Journal of Biological Chemistry.

[30]  A. Carr.  HIV protease inhibitor-related lipodystrophy syndrome. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  M. Bogyo,et al.  How an Inhibitor of the HIV-I Protease Modulates Proteasome Activity* , 1999, The Journal of Biological Chemistry.

[32]  J. Stoker,et al.  The Department of Health and Human Services. , 1999, Home healthcare nurse.

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

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

[35]  I. Shimomura,et al.  Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. , 1997, The Journal of clinical investigation.

[36]  D. Cooper,et al.  HIV protease inhibitors , 1996, AIDS.

[37]  J. Litz,et al.  Hormonal regulation of cholesterol 7 alpha-hydroxylase mRNA levels and transcriptional activity in primary rat hepatocyte cultures. , 1992, The Journal of biological chemistry.

[38]  P. Guzelian,et al.  Degradation of endogenous hepatic heme by pathways not yielding carbon monoxide. Studies in normal rat liver and in primary hepatocyte culture. , 1980, The Journal of clinical investigation.

[39]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.

[40]  A. Spector.  HIV protease inhibitors and hyperlipidemia: a fatty acid connection. , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[41]  P. Yeni.  Update on HAART in HIV. , 2006, Journal of hepatology.

[42]  J. Mallolas,et al.  Simultaneous determination of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma by reversed-phase high-performance liquid chromatography. , 2001, Journal of chromatography. B, Biomedical sciences and applications.