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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
Thesis (PhD)--Stellenbosch University, 2018.
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Stellenbosch : Stellenbosch University
2018
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| _version_ | 1867613809981521920 |
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| access_status_str | Open Access |
| author | Kamau, Festus Maina |
| author2 | Ruduwaan, Salie |
| author_browse | Kamau, Festus Maina Ruduwaan, Salie |
| author_facet | Ruduwaan, Salie Kamau, Festus Maina |
| author_sort | Kamau, Festus Maina |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2018. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/103335 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:42:03.173Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2018 |
| publishDateRange | 2018 |
| publishDateSort | 2018 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/103335 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 Kamau, Festus Maina Ruduwaan, Salie Waweru, Peter Maina Strijdom, Hans Stellenbosch University. Faculty of Medical and Health Sciences. Dept. of Biomedical Sciences : Medical Physiology. Highly active antiretroviral therapy (HAART) Nonalcoholic fatty liver disease (NAFLD) Cardiovascular system -- Diseases Peroxisome proliferator-activated receptor (PPAR) Obesity HIV/AIDS Insulin resistance Thesis (PhD)--Stellenbosch University, 2018. 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. Inleiding: Daar is ‘n daling in die HIV/VIGS sterftesyfer a.g.v. suksesvolle hoogs-aktiewe antiretrovirale terapie (HAART). Vetsug, nie-alkoholiese vetterige lewersiekte (NAFLD) en kardiovaskulêre siekte (KVS) in behandelde HIV-geïnfekteerde populasies is aan die styg. Ingekorte peroksisoom proliferator-geaktiveerde reseptor (PPARα/γ) funksie is deels hiervoor verantwoordelik. Doelwitte: Om die bydraes van ‘n protease inhibitor (Lopinavir/Ritonavir (LPV/r) en nukleosied omgekeerde transkriptase inhibitor (Azidothymidine (AZT)/lamivudine (3TC)) as deel van HAART in die ontwikkeling van NAFLD en KVS in rotte met ’n hoë kaloriedieet (HCD)-geïnduseerde vetsug te bepaal, asook tweeledige PPARα/γ-stimulasie in die vermindering van HAART-geïnduseerde NAFLD en KVS te bepaal. Metodes: Wistar rotte is lukraak in ‘n gewone rot-dieet en ‘n HCD groep (n=88/groep; 16 weke) ingedeel. Vanaf Week 10 is elke groep verder onderverdeel in: oplosmiddel/kontrole, HAART, HAART+PPARα/γ agonis (Saroglitazar) en slegs Saroglitazar (n=22/groep) wat via ‘n gastriese buis toegedien was. Eindpunte: Daaglikse kos/water verbruik, weeklikse totale liggaamsgewig (TBM), lukrake+vastende bloedglukose (n=8/groep); harte wat blootgestel is aan óf 20min globale isgemie/10min herperfusie, wat vir Western blot (WB) ontleding aangewend is, of 35min streeksisgemie/60min herperfusie (n=8/groep), wat vir hemodinamiese en infarktgrootte (IS) bepalings aangewend is. Lewermonsters is histologies ondersoek (n=12/groep) en ontleed deur WB. Intraperitoneale (IP) vet is geweeg. Vastende serumlipiede, oksidatiewe spanningsmerkers en insulien is gemeet (n=8/groep). WB ontledings van belangrike seintransduksieproteïene in pre/post-isgemiese hart-, lewer- en aortaweefsel uitgevoer. Torakale aortasegmente (n=8/groep) is aan isometriese spanningstudies blootgestel. Resultate: Die HCD het tot vetsug gelei (verhoogde: TBM, %IP vet (HCD kontrole 6.50±0.40% vs. gewone-dieet kontrole 3.60±0.3%; p<0.0001), lewermassa, insulien en trigliseriedes). Verder het HCD tot insulienweerstandigheid (IR) gelei. HAART+Saroglitazar het tot verlaagde %IP vet in kontrole en HCD groepe gelei. HAART het IR veroorsaak, terwyl verhoogde hartmassa en insulien in vetsugtige rotte deur kobehandeling met Saroglitazar verlaag is. HCD+HAART het vrye-vetsuur-oksidasie (verhoogde gekonjugeerde diëne) geïnduseer, wat deur gekombineerde HAART+Saroglitazar verminder is. Lewerhistologie: HAART het matige lewersteatose in ~67% van vetsugtige rotte en matige inflammasie in ~25% veroorsaak. Hierdie veranderinge is deur gekombineerde HAART+Saroglitazar verlig en AMPK en PKB/Akt aktiwiteit is opgereguleer, wat deur HAART afgereguleer is. Hart/aorta studies: Onbehandelde vetsugtige rotte het kleiner IS as kontrole gehad (19.1±1.6 vs. 26.1±1.6, onderskeidelik; p<0.05). Die IS vir rotte op HAART+HCD was kleiner (ondanks swak hartfunksie) vs. hul onbehandelde eweknieë. Die post-isgemiese aktiwiteit van Erk1/2, PKB/Akt, AMPK en eNOS is afgereguleer, terwyl uitdrukking van p22-phox en kaspase-3 verhoog is. Die uitdrukking van Erk1/2, PKB/Akt, AMPK en eNOS is deur HAART+Saroglitazar opgereguleer (1.5-voudig) en PKB/Akt en p22-phox is afgereguleer. Vetsugtige+HAART rotte het swak aortiese verslapping getoon ~30%, wat met afgereguleerde eNOS en PKB/Akt en opgereguleerde p22-phox geassosieer was. Tog het Saroglitazar+HAART in vetsugtige rotte tot verbeterde aortiese verslapping, gepaard met opgereguleerde eNOS en PKB/Akt, asook afgereguleerde p22-phox gelei. Bespreking en gevolgtrekking: HAART-geïnduseerde lewersteatose en KVS in vetsugtige rotte is deur ko-behandeling met ʼn PPARα/γ agonis verlig. HAART per se was nie ‘n kardiovaskulêre risikofaktor nie, maar het die HCD-geïnduseerde kardiovaskulêre effekte vererger. Dis noodsaaklik om die kardiovaskulêre risikofaktore in vetsugtige+HAART pasiënte te monitor, en ons bevindinge toon dat ko-behandeling met PPARα/γ agoniste terapeutiese potensiaal het. Die metaboliese, funksionele en seintransduksieversteurings in die lewer, hart en aortaweefsel in vetsugtige+HAART rotte is ineengeskakel en word gedeeltelik verlaag deur ko-behandeling met ‘n tweeledige PPARα/γ agonis. Doctoral 2018-01-18T14:17:10Z 2018-04-09T06:53:11Z 2018-01-18T14:17:10Z 2018-04-09T06:53:11Z 2018-03 Thesis http://hdl.handle.net/10019.1/103335 en_ZA Stellenbosch University 243 pages application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Highly active antiretroviral therapy (HAART) Nonalcoholic fatty liver disease (NAFLD) Cardiovascular system -- Diseases Peroxisome proliferator-activated receptor (PPAR) Obesity HIV/AIDS Insulin resistance Kamau, Festus Maina 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Highly active antiretroviral therapy (HAART) Nonalcoholic fatty liver disease (NAFLD) Cardiovascular system -- Diseases Peroxisome proliferator-activated receptor (PPAR) Obesity HIV/AIDS Insulin resistance |
| url | http://hdl.handle.net/10019.1/103335 |
| work_keys_str_mv | AT kamaufestusmaina contributionofhighlyactiveantiretroviraltherapytothedevelopmentofnonalcoholicfattyliverdiseasewithconcomitantcardiovasculardysfunctioninanobeseratmodel |