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HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitor-induced hyperlipidemia

Nature Medicine volume 7, pages 1327–1331 (2001)Cite this article

Abstract

Highly active anti-retroviral therapies, which incorporate HIV protease inhibitors, resolve many AIDS-defining illnesses. However, patients receiving protease inhibitors develop a marked lipodystrophy and hyperlipidemia. Using cultured human and rat hepatoma cells and primary hepatocytes from transgenic mice, we demonstrate that protease inhibitor treatment inhibits proteasomal degradation of nascent apolipoprotein B, the principal protein component of triglyceride and cholesterol-rich plasma lipoproteins. Unexpectedly, protease inhibitors also inhibited the secretion of apolipoprotein B. This was associated with inhibition of cholesteryl-ester synthesis and microsomal triglyceride transfer-protein activity. However, in the presence of oleic acid, which stimulates neutral-lipid biosynthesis, protease-inhibitor treatment increased secretion of apolipoprotein B-lipoproteins above controls. These findings suggest a molecular basis for protease-inhibitor–associated hyperlipidemia, a serious adverse effect of an otherwise efficacious treatment for HIV infection.

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Figure 1: PI treatment results in the accumulation of cellular ApoB and ubiquitin-associated ApoB in HepG2 cells.
Figure 2: PI treatment results in marked alterations in neutral-lipid synthesis and transfer.
Figure 3: PI treatment increases net secretion of ApoB-containing lipoproteins in the presence of added fatty acids.
Figure 4: RTV increases the secretion and buoyant density of ApoB-containing lipoproteins in McA RH7777 cells.
Figure 5: RTV-inhibition of apoB secretion and neutral lipid synthesis is reversed by oleic acid in cultured primary hepatocytes from ApoB transgenic mice.

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Acknowledgements

We thank N. Buss for the PIs used in this study; J. Billheimer for rat liver microsomes; and J. D. Rich and S. Santos for encouragement at the early stages of this work. This study was supported by Glaxo–Wellcome, Roche Products (Australia) and Merck and Company (to D.C.), NIH HL55638 (to H.G.), HL40404 (to R.J.D.) and the Columbia-Rockefeller Center for AIDS Research (NIH P30 AI42848 pilot award to S.L.S., R.J.D. and J.L.). R.J.D. and S.L.S. were supported in part by NIH HL65954 to N. S. Shachter. NCHECR is supported by the Research Advisory Committee of the Australian National Council on AIDS, Hepatitis C and Related Diseases through the Commonwealth Department of Health and Aged Care.

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  1. Jun-Shan Liang and Oliver Distler: J-S.L. and O.D. contributed equally to this study

Authors and Affiliations

  1. Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Jun-Shan Liang & Henry N. Ginsberg

  2. Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Richard J. Deckelbaum & Stephen L. Sturley

  3. Institute of Human Nutrition, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Oliver Distler, Richard J. Deckelbaum & Stephen L. Sturley

  4. National Center in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia

    Oliver Distler & David A. Cooper

  5. Bristol Myers Squibb, Princeton, New Jersey, USA

    Haris Jamil

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Correspondence to Stephen L. Sturley.

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Liang, JS., Distler, O., Cooper, D. et al. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 7, 1327–1331 (2001). https://doi.org/10.1038/nm1201-1327

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