Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats

Background: Although highly active antiretroviral therapy (HAART) is effective in the management of HIV, it has been reported to induce hepatic injury and non-alcoholic fatty liver (NAFLD). However, there is a lack of data on the roles of the adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway and caspase 3 signaling in HAART-induced NAFLD. Also, whether or not zinc confers protection against HAART-induced NAFLD is not known. Aim: This study evaluated the involvement of the ADA/XO/UA pathway and caspase 3 signaling in HAARTinduced hepatic lipid accumulation. It also evaluated the possible protective effect of zinc in HAART-induced hepatic lipid accumulation and injury. Methods: Thirty two male Wistar rats (n = 8/group) were assigned into four groups namely; vehicle-treated (p.o), zinc-treated (3 mg/kg/day of elemental zinc; p.o), HAART-treated (a cocktail of 52.9 mg/kg of Efavirenz, 26.48 mg/kg of Lamivudine, and 26.48 mg/kg of Tenofovir; p.o), and HAART + zinc-treated groups. The treatment lasted for 8 weeks. Results: HAART administration led to increased body weight and hepatic weight, but unaltered hepatic organosomatic index. HAART exposure also resulted in impaired glucose homeostasis, evidenced by increased fasting blood glucose, hyperinsulinemia, and insulin resistance (IR), increased plasma and hepatic cholesterol and triglycerides, and impaired hepatic function as depicted by elevated hepatic injury markers and reduced glycogen synthase activity and glycogen content. These findings were accompanied by increased plasma and hepatic ADA and XO activities, UA and malondialdehyde levels, inflammatory markers, and caspase 3 activities. However, HAART suppressed plasma and hepatic antioxidant defenses. Furthermore, HAART distorted hepatic histoarchitecture and reduced hepatic sinusoidal diameter. Co-administration of zinc with HAART normalized HAART-induced alterations. Conclusions: These findings showed that downregulation of the ADA/XO/UA pathway and caspase 3 signalings may rescue the liver from HAART-induced lipid accumulation and injury.

Automated summary

This study evaluated the involvement of the ADA/XO/UA pathway and caspase 3 signaling in HAART-induced hepatic lipid accumulation and found that downregulation of these pathways may rescue the liver from HAART-induced injury. Zinc may also confer protection against HAART-induced liver lipid accumulation and injury.