title: Prevention of HIV protease inhibitor-induced dysregulation of hepatic lipid metabolism by raltegravir via endoplasmic reticulum stress signaling pathways.
abstract: Hyperlipidemia associated with the HIV protease inhibitor (PI), the major component of highly active antiretroviral treatment (HAART) for HIV infection, has stimulated interest in developing new agents that minimize these side effects in the clinic. HIV integrase inhibitor is a new class of anti-HIV agents. Raltegravir is a first-in-its-class oral integrase inhibitor and has potent inhibitory activity against HIV-1 strains that are resistant to other antiretroviral regimens. Our previous studies have demonstrated that HIV PI-induced endoplasmic reticulum (ER) stress links to dysregulation of lipid metabolism. However, little information is available as to whether raltegravir would have similar effects as the HIV PIs. In this study, we examined the effect of raltegravir on lipid metabolism both in primary rat hepatocytes and in in vivo mouse models, and we further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed development of dyslipidemia. The results indicated that raltegravir did not induce ER stress or disrupt lipid metabolism either in vitro or in vivo. However, HIV PI-induced ER stress and lipid accumulation were significantly inhibited by raltegravir both in in vitro primary rat hepatocytes and in in vivo mouse liver. High-performance liquid chromatography analysis further demonstrated that raltegravir did not affect the uptake and metabolism of HIV PIs in hepatocytes. Thus, raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of lipid metabolism by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the side effects associated with current HAART.
authors.affiliation: School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Risheng
authors.initials: R
authors.lastname: Cao
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Emily C
authors.initials: EC
authors.lastname: Gurley
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Studer
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004336:Drug Antagonism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006949:Hyperlipidemias / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D061466:Lopinavir; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011744:Pyrimidinones / Q000009:adverse effects; D011760:Pyrrolidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D051381:Rats; D019438:Ritonavir / Q000009:adverse effects; D015398:Signal Transduction
chemical_list: D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D011760:Pyrrolidinones; D061466:Lopinavir; D000068898:Raltegravir Potassium; D019438:Ritonavir
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