Magnesium Supplementation Attenuated Lipogenic and Oxidative/Nitrosative Gene Expression Caused by Anti-HIV Drug Therapy in HIV-1-Transgenic Rats

The objective of this study is to determine if Mg supplementation might attenuate the systemic oxidative/nitrosative stress and lipogenic effects at the transcriptome level caused by a clinically used cART in a HIV-1 transgenic rat (Tg) model.A PI-based cART (atazanavir-ritonavir plus Truvada) was given orally to control and HIV-1-Tg rats at doses similar to the human equivalent for 18 weeks. A 6 fold higher than normal MgO in the diet was introduced to determine the effect of Mg supplementation. Relative Expressions of selected oxidative/nitrosative and lipogenic genes from livers were determined by real-time quantitative PCR and the expression levels of genes were quantified with values normalized by 18s rRNA. Under cART treatment, a 4-fold upregulation of the Sterol regulatory element-binding protein-1 (SREBP-1) gene was found in the Tg rats; SREBP-1 is a key transcription factor required for cholesterol and fatty acid biosynthesis. This upregulation was completely prevented by Mg supplementation. Nrf2, which is a master transcription factor that regulates the expression of antioxidant proteins, was down-regulated 50% in the HIV-Tg rats, and was further reduced to 25% in Tg+cART rats. Next, two selected downstream responsive genes, heme oxygenase-1 (HMOX1) and Glutathione S-transferase (GST) were examined. Both HMOX1 and GST, which are protective antioxidants genes, were elevated in HIV-Tg alone but were suppressed dramatically by cART. Both HIV and cART induced down-regulation of Nrf2 was attenuated, and changes in expressions of HMOX1 and GST were reversed by Mg-supplementation. Concomitantly, inducible NOS (iNOS) was upregulated 2-fold in the Tg+cART rats, which was normalized by Mg-supplementation. Correspondently, cART treatment led to increases in plasma 8-isoprostane (lipid peroxidation indicator) levels in both control and HIV-1-Tg rats. These elevations were lowered by Mg-supplementation. In addition, significantly higher level of plasma nitrotyrosin was found in the cART-Tg group; such elevation was suppressed in cART-Tg rats plus Mg-supplementation. Furthermore, both plasma triglyceride and cholesterol level were elevated in cART–Tg group, which again were lowered by Mg- supplementation.In summary, the lipogenic and oxidative/nitrosative effects that caused by cART in the HIV-1-TG rats were confirmed by the qPCR and biochemical data. The downstream regulation by Nrf2 confirmed that the antioxidant response in the HIV animals wasseverely compromised. However, these abnormal metabolic and oxidative stress effects were substantially attenuated by Mg-supplementation.

Author

• Elzohary, Lama

Language

• en

Keyword

• HIV-1 infection
• Anti-HIV drugs
• Mg protection.
• Oxidative/Nirtosative stress
• Lipogenesis

Date created

• 2017

Type of Work

• Master's Thesis

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Molecular Biochemistry & Bioinformatics

Degree

• M.S.

Advisor

• Mak, Iu Tong

Committee Member(s)

• Dimri, Goberdhan
• Mak, Iu Tong

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/8c97kq46t