Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Cao, Risheng; Hu, Yiqiao; Wang, Yun; Gurley, Emily C.; Studer, Elaine; Wang, Xuan; Hylemon, Phillip B.; Pandak, William M.; Sanyal, Arun J.; Zhang, Luyong; Zhou, Huiping

doi:10.1124/jpet.110.168484

Cited by 26 publications

(25 citation statements)

References 37 publications

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“…One potential pathway mediated by HIF-1α was suggested by Parathath et al [46] and Manalo et al [47]. Endoplasmic reticulum stress may also participate in regulation of lipid metabolism [48,49,50,51]. …”

Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Dysregulation of Lipid Metabolism in HepG2 Cells via Activation of HIF-2a

Cao

Zhao

et al. 2014

Cell Physiol Biochem

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Background: Hypoxia is a risk factor for non-alcoholic fatty liver diseases, leading to permanent imbalance of liver lipid homeostasis and steatohepatitis. The current study examined the effect of HIF-2α, an oxygen-sensitive heterodimeric transcription factor, on hypoxia-induced dysregulation of lipid metabolism in HepG2 cells. Methods: Studies were conducted in C57BL/6 male mice and human HepG2 cells under hypoxic conditions, transfected with HIF-2α-targeted shRNA. The mRNA and protein expressions of key genes relevant to lipid metabolism were determined via RT-qPCR and western blot, respectively. Intracellular lipid accumulation was determined by Nile red, filipin staining and quantitative assay kits. Results: HIF-2α protein was quantified in both HepG2 cells and C57BL/6 mice under hypoxic conditions. Intracellular lipid accumulation and increased lipid levels induced by hypoxia were significantly reduced by silence of HIF-2α expression, associated with reversed expression of ABCA1 and ADRP, key genes in involved cholesterol excretion and fatty acid uptake respectively. However, HIF-2α had no effect on enzymatic activity and expression of key genes involved in fatty acid β-oxidation or cholesterol metabolism. Conclusion: Inhibition of HIF-2α protein reversed lipid metabolism dysregulation induced by acute hypoxia in HepG2 cells, which suggested that HIF-2α signaling may be relevant to oxygen-dependent lipid homeostasis in the liver.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Dysregulation of Lipid Metabolism in HepG2 Cells via Activation of HIF-2a

Cao

Zhao

et al. 2014

Cell Physiol Biochem

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“…The intracellular levels of total cholesterol, free cholesterol, triglyceride, were measured using free cholesterol, cholesterol E and triglyceride assay kits (Wako Bioproducts, Richmond, VA) and normalized by total protein amount as described previously [15].…”

Section: Methodsmentioning

confidence: 99%

Reduction of the HIV Protease Inhibitor-Induced ER Stress and Inflammatory Response by Raltegravir in Macrophages

et al. 2014

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BackgroundHIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART-associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in-its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages.Methodology and Principal FindingsIn this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages.Conclusion and SignificanceRaltegravir could prevent HIV PI-induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART.

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“…However, the heightened risk of CVD persists even in the current treatment era, in which new generation ART have significantly reduced dysmetabolic side effects (e.g. insulin resistance, dyslipidemia, and hypertension) [19, 20]. …”

Section: Cardiovascular Disease (Cvd) As a Severe Complication In Hivmentioning

confidence: 99%

Increased cardiovascular disease risk in the HIV-positive population on ART: potential role of HIV-Nef and Tat

Wang¹,

Yi²,

Green³

et al. 2015

Cardiovascular Pathology

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With effective antiretroviral therapy (ART), many HIV-infected people die of diseases other than acquired immune deficiency syndrome (AIDS). In particular, coronary artery disease has emerged as one of most critical complications of HIV infection and a major cause of morbidity and mortality. Although reportedly antiretroviral combination therapy itself may accelerate atherosclerosis by enhancing dyslipidemia, most recent epidemiological studies support the notion that HIV infection itself contributes to cardiovascular disease. However, it is still a mystery how the virus can contribute to cardiovascular disease development even while suppressed by ARTs. This review discusses the current understanding of interactions between HIV infection and cardiovascular diseases in both clinical and experimental studies with special focus on those viral proteins which are still produced by HIV. This will help infectious disease/vascular biology experts to gain insights into the pathophysiological mechanisms of HIV associated cardiovascular disease and new trends to treat and prevent cardiovascular disease in the HIV infected population.

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Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Cited by 26 publications

References 37 publications

Hypoxia Induces Dysregulation of Lipid Metabolism in HepG2 Cells via Activation of HIF-2a

Hypoxia Induces Dysregulation of Lipid Metabolism in HepG2 Cells via Activation of HIF-2a

Reduction of the HIV Protease Inhibitor-Induced ER Stress and Inflammatory Response by Raltegravir in Macrophages

Increased cardiovascular disease risk in the HIV-positive population on ART: potential role of HIV-Nef and Tat

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