TY - JOUR
T1 - Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications
AU - Tsai, Fuu Jen
AU - Ho, Mao Wang
AU - Lai, Chih Ho
AU - Chou, Chen Hsing
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
N1 - Funding Information:
This study was based in part on data obtained from the National Health Insurance Research Database (NHIRD) provided by the Bureau of National Health Insurance, Department of Health and managed by the National Health Research Institutes (NHRI). The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Department of Health or NHRI. The authors wish to thank the Aim for Top University Plan of the Ministry of Education, Taiwan, at China Medical University. We also thank Dr. Kuan-Teh Jeang and Willy W. L. Hong for their technical help and suggestions. This study was supported by grants from China Medical University [CMU102-PH-01 and CMU100-S-01], China Medical University Hospital [DMR-105-031, DMR-105-098, and DMR-106-155], the National Science Council, the Ministry of Science and Technology, Taiwan [MOST 103-2320-B-039-006-MY3, MOST 105-2314-B-039-037-MY3, and MOST 106-2320-B-039-017-MY3], and China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan.
Publisher Copyright:
© 2018 Tsai, Ho, Lai, Chou, Li, Cheng, Wu, Liu, Tsang, Lin, Liao, Huang, Lin, Lin, Hsieh, Liang and Lin.
PY - 2018/9/4
Y1 - 2018/9/4
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.
AB - 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.
KW - Antiretroviral drug
KW - HIV-1
KW - Lipodystrophy
KW - Metabolic syndrome
KW - Neurologic function
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U2 - 10.3389/fphar.2018.01004
DO - 10.3389/fphar.2018.01004
M3 - Article
AN - SCOPUS:85053162081
SN - 1663-9812
VL - 9
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
IS - SEP
M1 - 1004
ER -
