Prevention of HIV protease inhibitor-induced dysregulation of hepatic lipid metabolism by raltegravir via endoplasmic reticulum stress signaling pathways.
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.
Cao
Risheng
R
School of Life Sciences, Nanjing University, Nanjing, China.
Hu
Yiqiao
Y
Wang
Yun
Y
Gurley
Emily C
EC
Studer
Elaine J
EJ
Wang
Xuan
X
Hylemon
Phillip B
PB
Pandak
William M
WM
Sanyal
Arun J
AJ
Zhang
Luyong
L
Zhou
Huiping
H
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
D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D011760:Pyrrolidinones; D061466:Lopinavir; D000068898:Raltegravir Potassium; D019438:Ritonavir
Clin Ther. 2008 Oct;30(10):1747-65
19014832
Semin Liver Dis. 2007 Nov;27(4):367-77
17979073
HIV Clin Trials. 2009 Jul-Aug;10(4):233-53
19723611
N Engl J Med. 2008 Jul 24;359(4):339-54
18650512
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 May 15;867(2):277-81
18434263
Am J Gastroenterol. 1999 Sep;94(9):2467-74
10484010
Atherosclerosis. 2007 Nov;195(1):e134-43
17531241
Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):7-9
16373621
Rev Med Virol. 2007 Jul-Aug;17(4):277-95
17503547
Mol Pharmacol. 2005 Jun;67(6):1909-19
15755908
Gastroenterology. 2010 Jan;138(1):197-209
19732776
J Biol Chem. 2001 Oct 5;276(40):37514-9
11546771
HIV Clin Trials. 2002 Jan-Feb;3(1):89-98
11894812
J Acquir Immune Defic Syndr. 2009 Nov 1;52(3):382-6
19654552
Diabetes. 2003 Jul;52(7):1695-1700
12829635
Cell. 2006 Feb 10;124(3):587-99
16469704
Diabetes. 2002 Apr;51(4):937-42
11916910
J Biol Chem. 1957 May;226(1):497-509
13428781
Clin Infect Dis. 2008 Jul 1;47(1):137-40
18513146
Nat Cell Biol. 2003 Sep;5(9):781-92
12907943
J Lipid Res. 2009 Apr;50 Suppl:S412-6
19074370
Expert Opin Pharmacother. 2009 Oct;10(15):2445-66
19678794
AIDS. 2001 Sep 28;15(14):1811-22
11579243
Biochem Biophys Res Commun. 2009 Aug 14;386(1):96-100
19501568
Am J Physiol Gastrointest Liver Physiol. 2006 Dec;291(6):G1071-80
16861219
Drugs R D. 2007;8(3):155-68
17472411
AIDS Patient Care STDS. 2008 Nov;22(11):917
19043838
Antimicrob Agents Chemother. 2008 Dec;52(12):4338-43
18838589
J Mol Neurosci. 2009 Sep;39(1-2):157-68
19145491
Biochem Biophys Res Commun. 2006 Nov 3;349(4):1406-11
16979584
Clin Pharmacol Ther. 2008 Feb;83(2):293-9
17713476
Drug Metab Dispos. 2007 Sep;35(9):1657-63
17591678
Mol Pharmacol. 2005 Sep;68(3):690-700
15976036
Hepatology. 2008 Jun;47(6):1905-15
18452148
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1178-84
12738681
AIDS. 2002 Apr 12;16(6):859-63
11919487
HIV Med. 2001 Jul;2(3):166-73
11737397
AIDS. 2007 Oct 18;21(16):2183-90
18090045