Evaluation of Oral Antiretroviral Drugs in Mice With Metabolic and Neurologic Complications.

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

doi:10.3389/fphar.2018.01004

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.

Highlights

With the current increasing use of a combination of antiretroviral (ART) drugs, HIV-1/AIDS has become a treatable, chronic disease and patients can expect improved overall health and life span (Deeks et al, 2013)
Adipogenic differentiation markers and transcription factors including fatty acid binding protein 4 (FABP4), adiponectin (Adipoq), peroxisome proliferatoractivated receptor-gamma (PPARg), lipoprotein lipase (Lpl), sterol regulatory element-binding protein-1 (SREBP-1), CCAAT enhancer-binding proteins (CEBPs), and fatty acid synthetase (FAS) in adipose tissues may contribute to adipogenesis (Kim et al, 1998; Rosen and Spiegelman, 2000; Gougeon et al, 2004; Chen et al, 2017)
Our study demonstrates that Taiwanese HIV-1-infected patients who received an nucleoside analog reverse transcriptase inhibitors (NRTIs)/NRTI-containing regimen had the highest hyperlipidemia risk, followed by patients receiving a protease inhibitors (PIs)-containing regimen (Tsai et al, 2017)

Summary

Introduction

With the current increasing use of a combination of antiretroviral (ART) drugs, HIV-1/AIDS has become a treatable, chronic disease and patients can expect improved overall health and life span (Deeks et al, 2013). ART treatment of HIV-1-infected patients has been associated with an increased risk of metabolic consequences, lipodystrophy syndrome, and neuropsychiatric complications (Jevtovic et al, 2009; Paula et al, 2013; Finkelstein et al, 2015; Pedrol et al, 2015). Several drugs including thiazolidinediones and leptins have ameliorated symptoms in patients on ART (Mulligan et al, 2009; Edgeworth et al, 2013; Tsoukas et al, 2015). Thiazolidinediones are a class of PPAR agonists, that upregulate PPAR-dependent genes such as adiponectin, and showed a beneficial effect on limb fat mass in HIV-1/ART-associated lipodystrophy syndrome patients (Edgeworth et al, 2013). Further investigation is needed into the effects of these ART drugs and their action mechanisms

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