Naringin abrogates HIV-1 protease inhibitors-induced atherogenic dyslipidemia and oxidative stress in vivo

Highlights

• Naringin reduced TC, TG, LDL-c, VLDL-c, AIP, increased HDL-c in PI-treated rats.

• Naringin reduced the protein levels of HMG-CoA and ACAT in PI-treated rats.

• Naringin reduced MDA concentrations, increased GSH, MDA, CAT in PI-treated rats.

• Naringin prevents HIV PIs-induced dyslipidemia and oxidative stress in vivo.

Abstract

Protective effects of naringin against HIV-1 protease inhibitors (PIs)-induced dyslipidemia and oxidative stress were investigated in vivo. Male Wistar rats were orally treated daily with atazanavir {ATV; 133 mg/kg body weight (BW)}, saquinavir (SQV; 333 mg/kg BW), distilled water (3.0 ml/kg BW) and with or without naringin (NAR; 50 mg/kg BW) for 56 days, respectively. ATV or SQV significantly reduced body weights and plasma HDL cholesterol concentrations but increased total cholesterol, triglycerides, LDL-cholesterol, VLDL-cholesterol concentrations and calculated atherogenic index ratio, respectively. Furthermore, ATV or SQV treatment significantly increased lipid peroxidation and carbonyl proteins concentrations in plasma, liver and pancreas tissues but significantly reduced antioxidant activities in the liver and pancreas compared to the controls, respectively. However, naringin treatment significantly improved weight loss, dyslipidemia and oxidative stress in ATV- or SQV-treated rats, respectively. Naringin prevents HIV PIs-induced dyslipidemia and oxidative stress and may therefore mitigate PI-associated metabolic complications in HIV patients.

Introduction

Combination antiretroviral therapy (cART) has profoundly enhanced clinical outcomes in HIV-1 infections, leading to reduced mortality and morbidity (Panos et al., 2008, Yang et al., 2008). Antiretroviral agents in clinical practice include Nucleotide Reverse Transcriptase Inhibitors (NRTIs), (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine), Non-Nucleosides Reverse Transcriptase Inhibitors (NNRTIs), (etravirine, delavirdine, efavirenz and nevirapine), Protease Inhibitors (PIs), (atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir and tipranavir), Integrase Inhibitors, (raltegravir), Entry and/or Fusion inhibitors (FI), (maraviroc and enfuvirtide) (Arts and Hazuda, 2012, Thompson et al., 2010). In cART, two NRTIs and one of either NNRTI or PI or FI are used as a first-line treatment, depending on efficacy and tolerability as per the current World Health Organisation treatment guidelines (Adetokunboh et al., 2015, Arts and Hazuda, 2012). The introduction of fixed-dose combination of the same has further enhanced compliance and adherence to ARV therapy (Barnhart & Shelton, 2015). Unfortunately, despite significant gains in therapeutic outcomes, chronic use of these agents is associated with metabolic complications (Palios, Kadoglou, & Lampropoulos, 2012). HIV PI-based regimes in particular have been associated with dyslipidemia, lipodystrophy and insulin resistance which could potentially predispose patients to increased risks of developing diabetes and cardiovascular diseases in the long run (Palios et al., 2012, Paula et al., 2013).

Dyslipidemia, characterized by elevated plasma LDL-cholesterol (LDL-c), Triglycerides (TG) or both and reduced plasma HDL-cholesterol (HDL-c) concentrations has been attributed to chronic use of PIs (Manjunath et al., 2013, Talayero and Sacks, 2011) in addition to viral pathogenesis (Feeney & Mallon, 2011). Up to 50% of HIV patients treated with PIs have reportedly developed dyslipidemia depending on individual PIs and the duration of therapy (Anuurad et al., 2010, Chastain et al., 2015). Higher plasma TG concentrations have been reported in patients treated with ritonavir-containing regimes, while increased plasma total cholesterol has been reported in patients treated with all PI-containing regimes (Lu et al., 2011, Overton et al., 2012). The newer PIs such as atazanavir and darunavir, however, appear to have less deleterious effects on lipid metabolism, even when boosted with ritonavir (Anuurad et al., 2010, Overton et al., 2012).

Furthermore, the use of PIs causes increased cellular oxidative stress, which is widely implicated in the development of metabolic diseases by as yet poorly understood mechanisms (Wang et al., 2009, Zhang et al., 2014). Increased production of Reactive Oxygen Species (ROS) is known to cause auto-oxidation of nuclei acids, polyunsaturated fatty acids and proteins leading to increased production of malondialdehyde (MDA), carbonyl proteins, reduced glutathione and antioxidant enzyme activities which cause damage to plasma membrane and increased cell apoptosis (Sharma, Jha, Dubey, & Pessarakli, 2012).

Currently, there are no effective therapeutic interventions for PI-associated metabolic complications. Switching of antiretroviral agents, surgical manipulations, anti-dyslipidemic and anti-diabetic agents, hormone replacement therapy, exercise and nutritional therapy have been tried with limited successes (Chastain et al., 2015, D.T. Holmes et al., 2008). Naringin (4′,5,7-Trihydroxyflavanone-7-rhamnoglucoside) is a flavonoid derived from Citrus paradise, and has been shown to have anti-atherogenic, anti-dyslipidemic, free radical scavenging and antioxidant properties (Liang et al., 2001, Pu et al., 2012). We have recently reported that naringin reduced PI-associated oxidative stress and apoptosis in rat insulinoma cell line (RIN-5F cells) (Nzuza, Ndwandwe, & Owira, 2016) and that naringin prevents NRTI-associated metabolic complications by ameliorating oxidative stress and apoptosis in experimental animals (Oluwafeyisetan, Olubunmi, & Pmo, 2015). This study, therefore, postulates that naringin could ameliorate dyslipidemia and oxidative stress that cause disturbances in lipid metabolism in PI-treated rats in vivo.