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16. Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine

Author

Duncan, Marilyn J., Bruce-Keller, Annadora J., Conner, Clayton, Knapp, Pamela E., Xu, Ruquiang, Nath, Avindra, and Hauser, Kurt F.

Subjects
HIV infection -- Development and progression, HIV infection -- Genetic aspects, Genetic transcription -- Research, Morphine -- Health aspects, Circadian rhythms -- Research, Biological sciences
Abstract

Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their entrainment to a light-dark (LD) cycle, by using transgenic mice in which Tat expression in the brain was induced via a doxycycline (DOX)-sensitive, glial fibrillary-associated, protein-restricted promoter. Because opiate substance abuse, which shares comorbidity with HIV infection, also disrupts sleep, a final experiment assessed the effects of morphine exposure on circadian rhythms in wild-type and Tat transgenic mice. Mice housed in cages equipped with running wheels were fed chow with or without DOX. Experiment 1 revealed a small but significant (P < 0.05) difference between groups in the phase angle of entrainment and a 15% decrease in the wheel running in the DOX group (P < 0.005). During exposure to constant darkness, DOX did not alter the endogenous period length of the circadian rhythm. Experiment 2 investigated the effect of DOX on circadian rhythms in wild-type and Tat(+) mice during exposure to a normal or phase-shifted LD cycle, or morphine treatment without any change in the LD cycle. Tat induction significantly decreased wheel running but did not affect entrainment to the normal or shifted LD cycle. Morphine decreased wheel running without altering the phase angle of entrainment, and the drug's effects were independent of Tat induction. In conclusion, these findings suggest that chronic brain expression of Tat decreases locomotor activity and the amplitude of circadian rhythms, but does not affect photic entrainment or reentrainment of the murine circadian pacemaker. human immunodeficiency virus-acquired immunodeficiency syndrome; morphine; opioid drug abuse; locomotor activity; human immunodeficiency virus encephalitis

Published
2008

21. Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C

Author

Bradshaw, Emily L., Li, Xiang-An, Guerin, Theresa, Everson, William V., Wilson, Melinda E., Bruce-Keller, Annadora J., Greenberg, Richard N., Guo, Ling, Ross, Stuart A., and Smart, Eric J.

Subjects
Low density lipoprotein receptors -- Research, Ubiquitin-proteasome system -- Research, Macrophages -- Research, Biological sciences
Abstract

HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that a-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using a-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of a-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, [alpha]-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase C[alpha] (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis. CD36; macrophage; proteasome; low-density lipoprotein receptor

Published
2006

46. Adipose-specific ablation of Nrf2 transiently delayed high-fat diet-induced obesity by altering glucose, lipid and energy metabolism of male mice

Author

Zhang, Le, Dasuri, Kalavathi, Fernandez-Kim, Sun-Ok, Bruce-Keller, Annadora J, and Keller, Jeffrey N

Subjects
Original Article
Abstract

Nuclear factor E2-related factor 2 (NRF2) is a well-known master controller of the cellular adaptive antioxidant and detoxification response. Recent studies demonstrated altered glucose, lipid and energy metabolism in mice with a global Nrf2 knockout. In the present study, we aim to determine the effects of an adipose-specific ablation of Nrf2 (ASAN) on diet-induced obesity (DIO) in male mice. The 6-week-old adipose-specific Nrf2 knockout (NK) and its Nrf2 control (NC) mice were fed with either control diet (CD) or high-fat diet (HFD) for 14 weeks. NK mice exhibited transiently delayed body weight (BW) growth from week 5 to week 11 of HFD feeding, higher daily physical activity levels and preferential use of fat over carbohydrates as a source of energy at week 8 of the CD-feeding period. After 14 weeks of feeding, NK mice showed comparable results with NC mice with respect to the overall BW and body fat content, but exhibited reduced blood glucose, reduced number but increased size of adipocytes, accompanied with elevated expression of many genes and proteins in the visceral fat related to glucose, lipid and energy metabolism (e.g. Fgf21, Pgc1a). These results indicated that NRF2 is an important mediator for glucose, lipid and energy metabolism in adipose tissue, and ASAN could have beneficial effect for prevention of DIO during the early development of mice.

Published
2016

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