Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications

Fuu Jen Tsai, Mao Wang Ho, Chih Ho Lai, Chen Hsing Chou, Ju Pi Li, Chi Fung Cheng, Yang Chang Wu, Xiang Liu, Hsinyi Tsang, Ting Hsu Lin, Chiu Chu Liao, Shao Mei Huang, Jung Chun Lin, Chih Chien Lin, Ching Liang Hsieh, Wen Miin Liang, Ying Ju Lin

Research output: Contribution to journalArticle

Abstract

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

Original languageEnglish
Article number1004
JournalFrontiers in Pharmacology
Volume9
Issue numberSEP
DOIs
Publication statusPublished - Sep 4 2018

Fingerprint

Reverse Transcriptase Inhibitors
Nervous System
Nucleosides
Pharmaceutical Preparations
Protease Inhibitors
Acetyl-CoA Carboxylase
AMP-Activated Protein Kinases
Hyperlipidemias
HIV-1
Hepatocytes
Lopinavir
Lipids
Ritonavir
Adipogenesis
Lamivudine
Zidovudine
Leptin
Serum
Taiwan
Inbred C57BL Mouse

Keywords

  • Antiretroviral drug
  • HIV-1
  • Lipodystrophy
  • Metabolic syndrome
  • Neurologic function

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Tsai, F. J., Ho, M. W., Lai, C. H., Chou, C. H., Li, J. P., Cheng, C. F., ... Lin, Y. J. (2018). Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications. Frontiers in Pharmacology, 9(SEP), [1004]. https://doi.org/10.3389/fphar.2018.01004

Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications. / Tsai, Fuu Jen; Ho, Mao Wang; Lai, Chih Ho; Chou, Chen Hsing; Li, Ju Pi; Cheng, Chi Fung; Wu, Yang Chang; Liu, Xiang; Tsang, Hsinyi; Lin, Ting Hsu; Liao, Chiu Chu; Huang, Shao Mei; Lin, Jung Chun; Lin, Chih Chien; Hsieh, Ching Liang; Liang, Wen Miin; Lin, Ying Ju.

In: Frontiers in Pharmacology, Vol. 9, No. SEP, 1004, 04.09.2018.

Research output: Contribution to journalArticle

Tsai, FJ, Ho, MW, Lai, CH, Chou, CH, Li, JP, Cheng, CF, Wu, YC, Liu, X, Tsang, H, Lin, TH, Liao, CC, Huang, SM, Lin, JC, Lin, CC, Hsieh, CL, Liang, WM & Lin, YJ 2018, 'Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications', Frontiers in Pharmacology, vol. 9, no. SEP, 1004. https://doi.org/10.3389/fphar.2018.01004
Tsai, Fuu Jen ; Ho, Mao Wang ; Lai, Chih Ho ; Chou, Chen Hsing ; Li, Ju Pi ; Cheng, Chi Fung ; Wu, Yang Chang ; Liu, Xiang ; Tsang, Hsinyi ; Lin, Ting Hsu ; Liao, Chiu Chu ; Huang, Shao Mei ; Lin, Jung Chun ; Lin, Chih Chien ; Hsieh, Ching Liang ; Liang, Wen Miin ; Lin, Ying Ju. / Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications. In: Frontiers in Pharmacology. 2018 ; Vol. 9, No. SEP.
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AU - Tsai, Fuu Jen

AU - Ho, Mao Wang

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AU - Li, Ju Pi

AU - Cheng, Chi Fung

AU - Wu, Yang Chang

AU - Liu, Xiang

AU - Tsang, Hsinyi

AU - Lin, Ting Hsu

AU - Liao, Chiu Chu

AU - Huang, Shao Mei

AU - Lin, Jung Chun

AU - Lin, Chih Chien

AU - Hsieh, Ching Liang

AU - Liang, Wen Miin

AU - Lin, Ying Ju

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N2 - Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

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KW - Antiretroviral drug

KW - HIV-1

KW - Lipodystrophy

KW - Metabolic syndrome

KW - Neurologic function

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