Browsing by Author "Kamau, Festus Maina"

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    Contribution of highly active anti-retroviral therapy to the development of non-alcoholic fatty liver disease with concomitant cardiovascular dysfunction in an obese rat model
    (Stellenbosch : Stellenbosch University, 2018-03) Kamau, Festus Maina; Ruduwaan, Salie; Waweru, Peter Maina; Strijdom, Hans; Stellenbosch University. Faculty of Medical and Health Sciences. Dept. of Biomedical Sciences : Medical Physiology.
    Introduction: HIV/AIDS mortality is declining due to successful highly active anti-retroviral therapy (HAART). However, obesity, non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) in treated HIV-infected populations are rising. Impaired peroxisome proliferator-activated receptor (PPARα/γ) activity is partly implicated. Aims: To assess the contribution of a protease inhibitor (Lopinavir/Ritonavir (LPV/r) and nucleoside reverse transcriptase inhibitor (Azidothymidine (AZT)/lamivudine (3TC)) HAART regimen in the development of NAFLD and CVD in rats with high caloric diet (HCD)-induced obesity, and to investigate dual PPARα/γ stimulation in limiting HAART-induced NAFLD and CVD. Methods: Wistar rats were randomised into rat chow and HCD groups (n=88/group; 16 weeks). From week 10, each group was further sub-divided into: vehicle/control, HAART, HAART+PPARα/γ agonist (Saroglitazar) and Saroglitazar only (n=22/group) administered via oral gavage. Endpoints: Daily food/water consumption, weekly total body mass (TBM), random+fasting blood glucose measurements (n=8/group); hearts exposed to either 20min global ischaemia/10min reperfusion for Western blot (WB) analysis (n=6/group) or 35min regional ischaemia/60min reperfusion (n=8/group) for haemodynamic and infarct size (IS) determinations. Liver samples were histologically assessed (n=12/group) and analysed by WB. Intraperitoneal (IP) fat was weighed. Fasting serum lipids, insulin and oxidative stress markers were measured (n=8/group). WB analyses of important signalling proteins in pre/post-cardiac ischaemia, liver and aorta tissues. Thoracic aorta (n=8/group) segments were subjected to isometric tension studies. Results: The HCD resulted in obesity (increased: TBM, %IP fat (HCD control 6.50±0.40% vs. lean control 3.60±0.3%; p<0.0001), liver mass, insulin and triglycerides (TGs). Additionally, HCD induced insulin resistance (IR). HAART+Saroglitazar led to reduced %IP fat in lean and HCD groups. HAART-induced IR, elevated cardiac mass and insulin in obese rats were limited by Saroglitazar co-treatment. HCD+HAART-induced oxidative stress (elevated conjugated dienes), was limited in combined HAART+Saroglitazar. Liver histology: HAART induced moderate hepatic steatosis in ~67% of obese rats and moderate inflammation in ~25% of cases. Combined HAART+Saroglitazar limited these changes and upregulated adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (PKB/Akt) activity, which were downregulated by HAART in HCD. Heart/aorta studies: Untreated obese rats had smaller %IS compared to lean control rats (19.1±1.6 vs. 26.1±1.6, respectively; p<0.05). IS for HCD+HAART animals were smaller (despite poor cardiac performance) compared to untreated obese rats. Post-ischaemia activity of extracellular-signal-regulated kinase (Erk1/2), PKB/Akt, AMPK and endothelial nitric oxide synthase (eNOS) was downregulated, whereas expression of p22-phox and caspase-3 was accentuated. HAART+Saroglitazar upregulated (1.5-fold) the expression of Erk1/2, PKB/Akt, AMPK and eNOS, and downregulated caspase-3 and p22-phox. Obese+HAART rats demonstrated poor aortic relaxation accompanied by downregulated eNOS and PKB/Akt, and upregulated p22-phox. However, Saroglitazar+HAART in obese animals improved aortic relaxation by ~30%, accompanied by upregulation of eNOS, and PKB/Akt, and downregulated p22-phox. Discussion and conclusion: HAART-induced NAFLD and CVD in obesity were limited by PPARα/γ agonist co-administration. HAART treatment for six weeks was not a cardiovascular risk factor per se, but it potentiated HCD-induced cardiovascular effects. Monitoring cardiovascular risk factors in obese+HAART patients is crucial, and our findings suggest that there is therapeutic potential in co-treatment with PPARα/γ agonists. The metabolic, functional and signalling disturbances in the liver, heart and aorta tissues in obese+HAART rats are interlinked, and partially limited by co-treatment with a dual PPARα/γ agonist.