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.